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Akhtar and Veenstra Cell & Bioscience 2011, 1:23
http://www.cellandbioscience.com/content/1/1/23

REVIEW

Cell & Bioscience
Open Access

TBP-related factors: a paradigm of diversity in
transcription initiation
Waseem Akhtar and Gert Jan C Veenstra*

Abstract
TATA binding protein (TBP) is a key component of the eukaryotic transcription initiation machinery. It functions in
several complexes involved in core promoter recognition and assembly of the pre-initiation complex. Through
gene duplication eukaryotes have expanded their repertoire of TATA binding proteins, leading to a variable
composition of the transcription machinery. In vertebrates this repertoire consists of TBP, TBP-like factor (TLF, also
known as TBPL1, TRF2) and TBP2 (also known as TBPL2, TRF3). All three factors are essential, with TLF and TBP2
playing important roles in development and differentiation, in particular gametogenesis and early embryonic
development, whereas TBP dominates somatic cell transcription. TBP-related factors may compete for promoters
when co-expressed, but also show preferential interactions with subsets of promoters. Initiation factor switching
occurs on account of differential expression of these proteins in gametes, embryos and somatic cells. Paralogs of
TFIIA and TAF subunits account for additional variation in the transcription initiation complex. This variation in core
promoter recognition accommodates the expanded regulatory capacity and specificity required for germ cells and
embryonic development in higher eukaryotes.
Introduction
Eukaryotic cells have three RNA polymerases: RNA polymerase I (RNAP-I) transcribes the ribosomal RNA genes,
RNAP-II mostly transcribes protein-coding genes and
some non-coding genes, whereas RNAP-III generally transcribes small RNA genes. The RNA polymerases, however,
do not have the ability to recognize the proper sites of
transcription initiation. For the recruitment of each RNA
polymerase to the site of initiation, an additional set of
polypeptides is required, the basal transcription factors.
These proteins recognize the core promoter, a sequence of
approximately 100 bp around the transcription start site
that is required for initiation of transcription and which
contains specific sequence motifs, such as the TATA box,
Initiator (Inr) and Downstream Promoter Element (DPE)
[1]. The basal transcription factors for RNA polymerase II
(RNAP-II) include Transcription Factor II A (TFIIA),
TFIIB, TFIID, TFIIE, TFIIF and TFIIH (reviewed in [2])
which together with RNAP-II form the pre initiation complex (PIC). PIC formation typically starts with the recognition of the core promoter by TFIID, which consists of
* Correspondence: g.veenstra@ncmls.ru.nl
Radboud University Nijmegen, Department of Molecular Biology, Faculty of
Science, Nijmegen Centre for Molecular Life Sciences, Nijmegen, The
Netherlands

TATA box binding protein (TBP) and up to 14 other polypeptides called TBP-associated factors (TAFs) [2]. TFIID
and other basal transcription factors have been considered
a general set of proteins involved in transcription at all
RNAP-II promoters. However, TFIID is present in many
forms in different tissues and cell types. These forms have
different variants of TAFs as well as distinct additional
polypeptides ([3] and references therein). Similarly, in
many species TBP is not the universal initiation factor that
it is in yeast. Repeated gene duplication events have produced TBP-related factors in different species. In this
essay we discuss a new paradigm of versatility of the transcription machinery, which involves selective factor
recruitment as well as factor switching in the context of
the expanded regulatory complexity of germ cell and
embryonic development and differentiation.

TATA box binding protein (TBP)
TBP is the founding member of the family and is
involved in transcription by all of the three major RNA
polymerases (I, II and III) in eukaryotes [4]. It is conserved from archea to man. The primary structure of
TBP consists of two major domains. The core domain,
which is highly conserved (80% identical between yeast
and mammals) consists of two direct pseudo repeats and

© 2011 Akhtar and Veenstra; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.

Akhtar and Veenstra Cell & Bioscience 2011, 1:23
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folds into a saddle-shaped structure with a convex and a
concave surface (Figures 1, 2). The convex surface of this
saddle binds to the minor groove of the TATA box via
an induced fit model [5]. The N-terminal domain is relatively variable in sequence and size between species but
is conserved in vertebrates. TBP is the founding member
of small family of TBP paralogs in eukaryotic genomes
(Figure 2, 3).
Structure of TBP

High resolution crystal structures of the core domain of
TBP from different species have been solved [6-12].
These structural studies illustrate that the core domain
folds into a bipartite saddle like structure with approximate dimensions of 32 × 45 × 60 angstroms (Figure 1).
The saddle consists of two quasi-symmetric halves each
consisting of a five-stranded, anti-parallel curved b sheet
and two a helices that lie perpendicular to each other.
Four b strands from each half of the saddle form the
concave underside that binds to DNA. The four a
helices, two from each half of the saddle, the basic peptide that links the two quasi-symmetric domains and
parts of two b strands make up the convex upper side
of the saddle. This surface harbors the binding interfaces
for many proteins involved in the process of transcription initiation.
TATA box recognition by TBP

TBP binds to the TATA box via an induced-fit mechanism of protein-DNA recognition [8-10,12,13]. The DNA

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is highly bent and TBP also goes through a conformational change. The DNA enters the C-terminal portion of
TBP as a regular B-DNA conformation (corresponding to
the 5’-end of DNA) but then undergoes a transition into
a unique partially unwounded right-handed double helix
by a kink. This kink in DNA is caused by the insertion of
two phenylalanine residues (Phe284/Phe301 in human
TBP) into the minor groove between the first two base
pairs of the TATA box. A similar kink is produced at the
exit of the DNA from the other side by the insertion of
two other phenylalanine residues (Phe193/Phe210)
between the 7th and the 8th base pairs of the TATA box.
The second kink restores the DNA back to its usual BDNA conformation. In this way, while bound to TBP, the
middle six base pairs of the TATA box are in a partially
unwound right-handed double helical conformation with
a widened minor groove which fits in an energetically
favored manner to the concave surface. TBP binding to a
canonical TATA box proceeds via a two-step pathway;
first an unstable complex with unbent DNA is established. Second this complex is slowly converted into a
stable complex in which the DNA is bent [14]. The second step is greatly accelerated by TFIIB in cooperation
with an inhibitory DNA binding surface of TBP.
TBP complexes

TBP is part of a number of complexes which function
with different RNA polymerases. To function at RNAP-I
promoters, TBP joins the Selectivity factor 1 (SL1) complex together with five RNAP-I specific TAFs (reviewed

Figure 1 Structure of core domain of human TBP bound to the TATA element of the adenovirus major late promoter. The DNA is
shown in grey, TBP is shown in red. Amino acids that are different between TBP and TBP2 are shown in blue. Left: Frontal view, showing that
all amino acids contacting the DNA are identical between TBP and TBP2 (red). Substituted amino acids are solvent exposed (blue). Right: Top
view, showing that TBP aligns with the minor groove in which it is inserted.

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Figure 2 Domain structure of the vertebrate TBP family. The
core domain (blue) is formed by an imperfect direct repeat (blue)
and is involved in binding to the TATA box in the case of TBP and
TBP2. TLF lacks an N-terminal domain. The N-terminal domain of
TBP2 is not as well conserved as the core domain. The PXT repeats
in the N-terminal domain are indicated (green), as well as the polyglutamine stretch of TBP (orange).

in [15]). TBP and two RNAP-III-specific TAFs (BrfI and
BdpI) assemble into the TFIIIB complex, which is
involved in RNAP-III transcription. In vertebrates, there
are two versions of TFIIIB complex containing either BrfI
or its homolog BrfII (reviewed in [16]). Besides TFIIIB,
TBP also interacts with the snRNA activating protein
complex (SNAPc) at the human U6 promoter [17]. At
many RNAP-II promoters TBP works in a large complex
called TFIID, which contains in addition to TBP approximately 14 evolutionarily conserved distinct RNAP-II specific TAFs (reviewed in [18,19]). The TFIID complex
recognizes the RNAP-II core promoter as a result of
recognition of different core promoter elements by TBP
and TAFs and starts the nucleation of the PIC. Additionally, it also serves as a targeting interface for the binding
of many transcription activators. However, the activity of
TBP at RNAP-II promoters is also modulated through
the formation of alternative complexes as discussed in
the next paragraph.
Negative modulation of TBP activity

TATA boxes and AT-rich sequences are scattered over
the genome and TBP has a relatively low specificity for
binding to the TATA box. The affinity for its DNA element is ~1000 times lower than the proteins that bind the
major groove of DNA [20]. In addition, TBP has a very
low dissociation rate after it has bound to DNA. This
implies that there should be mechanisms in place to negatively modulate the ability of TBP to bind DNA as well as
to actively remove TBP from its DNA-bound state.
Two distinct domains in the N-terminal region of
TAF1, the largest subunit of TFIID, interact with TBP
and negatively modulate its ability to bind TATA box
[21]. TAF N-terminal domain 1 (TAND1) binds to the
concave surface of TBP and thus directly blocks DNA
binding [22]. Additionally, the TAND1 binding surface
also overlaps with the binding site of transcriptional activator VP16 resulting in a competition between the two
proteins to bind TBP [23]. TAND2 binds to an interface

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on the convex surface of TBP that is crucial for TFIIA
binding. Thus, TAND2 negatively influences the binding
of TBP with TFIIA [24], which otherwise would stabilize
binding of TBP to the TATA box.
TBP also forms a distinct complex involved in RNAP-II
transcription called B-TFIID, in which TBP interacts with
a unique TAF called BTAF1 (reviewed in [25]). It is
called Mot1 in yeast and is a Swi2/Snf2-related ATPase
that exerts both positive and negative effects on transcription [26-28]. Very much like TAF1, it also binds to
the concave and convex surface of TBP and thus modulates TBP binding to DNA and TFIIA respectively [29].
An important function of BTAF1 is to dissociate the
TBP-DNA complex using the energy of ATP hydrolysis
[30]. In this way BTAF1 can also clear TBP from spurious TATA boxes and redistribute it to bona fide promoters, which partially accounts for BTAF1’s ability to
positively affect transcription at some promoters [27,28].
Another well-known TBP complex is formed by its association with negative cofactor 2 (NC2). NC2 consists of
two subunits called NC2a (Dr1) and NC2ß (Drap1)
which are bound with each other via histone-fold
domains [31]. NC2 binds to free TBP as well as TBP
bound to DNA. The NC2-TBP-DNA ternary complex
locks the TBP in a state that is resistant to binding with
TFIIA and TFIIB [32]. NC2 and Mot1 were shown to
inhibit transcription from TATA-containing promoters
but stimulated the transcription from DPE-dependent
promoters [33,34]. Interestingly, the presence of a functional initiator sequence can provide resistance against
NC2-mediated transcriptional repression [35]. A genome
wide occupancy analysis in yeast has shown that TBP,
NC2, and Mot1 colocalize at transcriptionally active
RNAP-II core promoters. ATP hydrolysis by Mot1 disassembles this complex resulting in dissociation of TBP
from DNA suggesting that NC2 and Mot1 cooperate to
control the dynamics of TBP turnover in vivo [36]. Interestingly, this turnover of TBP at TATA box-containing
promoters (often associated with tightly regulated genes)
is faster in comparison to TATA-less promoters, implicating TBP removal in stringent regulation of transcription [37,38].
Role of N-terminal domain of TBP

TBPs from vertebrates contain a conserved N-terminal
domain (Figure 2). In vitro studies have shown that this
domain is important for TATA-containing RNAP-II and
III promoters but dispensable for TATA-less transcription [39]. Furthermore, this domain negatively modulates
the binding of the TATA box by the core domain and
mediates cooperative binding with SNAPc at the U6
promoter [14,40]. Contrary to these in vitro findings,
homozygous loss of most of the N-terminal domain has
no apparent effect on either cell growth or transcription

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Figure 3 Phylogenetic tree of the TBP-related factors in eukaryotes based on alignment of their core domains. TBP (gold) is the founding
member of the family with representatives in archae (not shown), yeast and all metazoans. TRF (TRF1, red) is found in the fruit fly and the mosquito.
TLF (TBPL1, TRF2, light green) is found in all multicellular organisms, but not in yeast. TBP2 (TBPL2, TRF3, blue) is restricted to vertebrates. The bar
signifies the distance in the tree corresponding to 10% divergence. Legend: hs-Homo sapiens, mm-Mus musculus, rn-Rattus norvegicus, xl-Xenopus
laevis, fr-Fugu rubripes, ci-Ciona intestinalis, dm-Drosophila melanogaster, ag-Anopheles gambiae, ce-Caenorhabditis elegans, sc-Saccharomyces cerevisiae.
ciTBP: XP_002127120, ciTLF: XP_002128047, ciTBP-like: BW175023, agTBP: XP_309748, agTRF1: XP_317373, agTRF2: XP_308361.

by RNAP-II and RNAP-III [41]. However, the N-terminal
domain plays an important role in post-transplantation
embryos to evade rejection by the maternal immune
response by repressing a b2 microglobin mediated process [42]. The mechanism underlying this phenomenon
remains to be elucidated. The N-terminal domain is also
clinically important as it features a glutamine repeat

region (Figure 2), the expansion of which results in
spino-cerebellar ataxia 17 (SCA17, reviewed in [43]).
TBP function through the cell cycle

Changes in TBP levels affect the transcription of genes
involved in the cell cycle. TBP expression is often elevated in Ras oncogene-transformed cells. Concordantly,

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stable over-expression of TBP leads to transformation of
cells [44,45]. Inversely, reduction of TBP levels to 50%
by inactivating one of its alleles in chicken DT40 lymphoid cells results in a decrease in the expression of
cdc25B phosphatase. This leads to an increase in hyperphosphorylated Cdc2 resulting in delayed cell cycle and
enhanced apoptosis [46]. In addition, TBP plays an
important role during mitosis in the transmission of
active gene memory to daughter cells [47,48]. The
underlying mechanism involves TBP-mediated recruitment of protein phosphatase 2A, which locally inactivates condensin via dephosphorylation and thus inhibits
compaction of transcriptionally active gene loci during
mitosis [48].
Requirement of TBP in early development

TBP mRNA is abundant in oocytes, but the encoded protein is not. The TBP messenger is translationally masked
in oocytes and is only translated during early cleavage
stages [49]. TBP protein levels peak at the Xenopus midblastula transition, at the onset of zygotic transcription.
Likewise, TBP protein only accumulates in 2-cell mouse
zygote, at the onset of mouse zygotic gene activation
[50,51] (Figure 4). Precocious translation of recombinant
TBP mRNA allows pre-MBT promoter activity in frog
embryos, but only in combination with competitor DNA,
which competes for chromatin assembly [49,52].
Not all transcription in early embryos (zebrafish, Xenopus, mouse) requires the presence of TBP [53-55]. Even
though TBP is essential, it is necessary for transcription
of only a small subset of genes in Xenopus embryos [56].
Also in mouse zygotes, not all transcription requires TBP
[53]. The other two vertebrate TBP-related factors (TBP2
and TLF) are not thought to be involved [53,57,58] so the
underlying mechanism of TBP-independent transcription
in mouse zygotes remains to be solved.
Some of the embryonic TBP-dependent genes regulate
degradation of maternal mRNAs through the miR-430
pathway in zebrafish [59]. The fact that TBP is not
expressed in the oocyte but is important for both the
onset of new transcription at the mid-blastula transition
and the degradation of maternal messages, implies that
this factor plays a crucial role in the transition from maternal to zygotic control of gene expression [59]. Many of the
transcripts that depend on TBP in the embryo are also
expressed maternally and in adult stages, have orthologs in
yeast, and show no functional specialization [56], suggesting that the founding member of the animal TBP family is
a relatively generic initiation factor that is required for
both embryonic and somatic cell transcription [56,59].

TBP-related factor
TBP-related factor (TRF, also known as TRF1) was the
first TBP paralog to be discovered in animals [60]. TRF1

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was discovered in a genetic screen of Drosophila and
turns out to be specific to insects (Figure 3). It is highly
expressed in embryonic central nervous system and
male germ cells [61]. It is 63% identical to TBP in the
core domain, can associate with the TATA box and stimulate basal transcription in vitro [62], whereas in vivo
it can direct transcription from one of the tudor gene
promoters [61]. Most of TRF1 is associated with the
Drosophila homolog of the RNAP-III specific transcription factor Brf1 [63] and TRF1-depleted Drosophila
Schneider line-2 cell extracts are unable to support
RNAP-III transcription. These observations were further
confirmed by genome-wide chromatin immunoprecipitation (ChIP) analysis, which shows that TRF1 is recruited
to a majority of RNAP-III and some RNAP-II promoters
in the fly genome [64]. Thus, in Drosophila cells, TFIIIB
activity (an essential ingredient of RNAP-III mediated
transcription) is accommodated by Brf1 and TRF1,
which is in clear contrast to the situation in yeast and
human cells where Brf1 is in a complex with TBP [65].

TBP-like factor
TBP-like factor (TLF, also known as TBPL1 and TRF2) is
a more distant paralog of TBP that is found in all
metazoans (Figure 3). It has only ~40% identity with the
TBP core domain [66] (Figure 2). It is the only member
of TBP family which lacks the ability to bind the TATA
box. It however, interacts with TFIIA and TFIIB [67-69].
Compared to TBP, TLF is less conserved between distinct species. The core domains of TLF are only 40-45%
identical in metazoans, whereas the TBP core domain is
80% identical from yeast to human [70]. TLF forms a
complex with TFIIA in HeLa cells but can also interact
with TFIIA-like factor (ALF), which is a germ cell-specific paralog of TFIIA [69,71,72]. TLF was also shown to
negatively modulate transcription by sequestering TFIIA
[73-75]. Surprisingly, the interaction of TLF with TFIIA
activates the transcription of the TATA-less neurofibromatosis type 1 gene [73]. On a similar note, chicken TLF
was shown to inhibit transcription from TATA-containing promoters but activate transcription from TATA-less
promoters [74].
The function of TLF has been studied in worm, frog
and fish using knockdown and dominant negative strategies [54,55,70,76]. In these organisms, ablation of TLF
function results in an early arrest of embryonic development and down regulation of a subset of genes. TLF
knockdown combined with transcriptome profiling in
frog embryos showed that a large number of transcripts
require TLF but not TBP or the vertebrate-specific paralog TBP2 [56]. A significant proportion of these genes is
preferentially expressed in embryos and shows a functional specialization in catabolism. A function in embryonic catabolism may be especially relevant in the light of

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Figure 4 Switching of TATA binding proteins between oocytes and embryos. (A) In Xenopus oocytes TBP2 but not TBP is present at the
protein level. Upon meiotic maturation (MM) TBP2 is degraded after global shut down of transcription, but residual levels of TBP2 persist in egg
and early embryo. During early cleavages after fertilization, maternal stores of TBP mRNA are translated and by the mid-blastula transition (MBT)
both TBP and residual TBP2 contribute to zygotic transcription leading to a partial switching of function between TBP and TBP2. In X. laevis TBP2
RNA is detected well into larval stages, whereas in X. tropicalis TBP2 mRNA levels decline during gastrulation (our unpublished data). (B) Mouse
oocytes also express only TBP2. When zygotic transcription commences at the two cell stage of the mouse embryo, TBP2 function is replaced by
translationally upregulated TBP leading to a complete switching of TATA binding factors.

the fact that TLF is important for externally developing
embryos (fly, fish, frog) whereas TLF is dispensable for
normal embryogenesis in mouse [58,77]. It is however,
required for proper spermatogenesis as male TLF-null
mice are sterile. This may suggest a functional specialization of TLF in different species. In TLF knockout mice
spermatogenesis is arrested when round spermatids
mature into elongated spermatids. TLF is required for
proper chromocenter formation in haploid round spermatids [78]. Several other lines of evidence also link TLF
to germ cell differentiation and proper chromatin

formation. In Drosophila embryos TLF has been reported
to be a part of a large protein complex containing components of nucleosome remodeling factor (NURF) complex and the fly-specific DNA replication element
binding factor (DREF) [79]. TLF promotes the transcription from an upstream promoter of proliferating cell
nuclear antigen (PCNA). This promoter has a DRE motif,
which is bound by DREF. Intriguingly, the DRE is among
the most prevalent core promoter elements in the Drosophila genome [80,81]. Two different isoforms of TRF2
were identified in Drosophila, however no differences in

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their expression pattern were observed indicating that
they perform similar functions [72]. Partial inactivation
of TLF in flies leads to defects in embryonic development, impaired premeiotic chromosome condensation
and defective differentiation of male and female germ
cells [72,82]. Furthermore, TLF depletion in Drosophila
salivary glands causes severe disruption of chromatin
structure in polytene chromosomes, again suggestive of a
link between TLF expression and proper chromatin function [83]. In Drosophila TLF controls the transcription
from one of the histone H1 genes, whereas the other histone genes in the cluster are TBP-dependent [83]. A genome-wide TLF occupancy analysis in Drosophila S2 cells
revealed that TLF is bound to more than a thousand sites
[83]. About 80% of these sites are not overlapping with
TBP binding regions suggesting that a fair number of
genes in Drosophila are controlled independently of TBP.
Interestingly, TLF binding sites are enriched for DREs
and are mostly lacking TATA boxes [83].
Taken together, TLF most likely provides an alternative
mechanism of transcription initiation. The details of this
alternative mechanism of initiation are not yet known
but may involve chromatin remodeling. A requirement
for TLF in germ cells is conserved from fly to mouse,
whereas TLF is also essential for early embryogenesis in
all non-mammalian metazoans examined (worm, fly, fish,
frog) but not in mouse.

TBP2
TBP2 (also known as TBPL2, TRF3) is the most recently
identified member of TBP family. It has only been found
in vertebrate genomes (Figure 3) and is the most closely
related TBP paralog showing 95% sequence identity in the
core domain (Figures 1, 2) [84,85]. It can bind to the
TATA box, interacts with TFIIA and TFIIB and promotes
basal transcription in vitro [84,85]. Although some early
reports suggested a widespread expression of TBP2, it has
become apparent that the main site of TBP2 expression is
in oocytes, with lower but detectable expression of TBP2
RNA and protein in early embryos and embryonic stem
cells, a pattern conserved in zebrafish, frog and mouse
[50,84-88]. The absence of TBP protein in oocytes and the
abundance of TBP2 in this cell type, suggested that TBP2
functions as a TBP replacement factor in oocytes [85].
TBP2 binds to the transcriptionally active loops of the
meiosis I lampbrush chromosomes of Xenopus oocytes
[86]. TBP2 promotes RNAP-II transcription in oocytes,
but ectopically expressed TBP can do the same, showing
that switching of initiation factors can be driven by expression levels in this system. Most of the oocyte TBP2 protein
is actively degraded during meiotic maturation of oocytes,
however, some residual maternal TBP2 remains in early
embryos [85,86] (Figure 4). The first functional studies in
fish and frog showed that TBP2 is indispensable for

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embryonic development [84,85]. A requirement for TBP2
is found particularly among vertebrate-specific genes
expressed during embryogenesis, implicating this initiation
factor in developmental innovation in vertebrates; TBP2 is
involved in ventral specification during frog development
[56]. A function for TBP2 has also been reported in differentiation pathways in zebrafish and mouse [89,90]. During
zebrafish embryogenesis, TBP2 binds and promotes transcription of the mespa gene, which encodes a transcription
factor that initiates a pathway required for the commitment of ventral mesoderm to the hematopoietic lineage
[90]. This function of TBP2 is dependent on its interaction
with TAF3 [91]. In contrast, TBP2 knockout mice are perfectly viable with no overt defects in embryogenesis or
somatic cell differentiation. Rather the loss of TBP2
severely affects oocyte folliculogenesis rendering female
Tbp2-/- mice sterile [57]. So in mouse the most physiologically relevant function of TBP2 is in oocytes where it is
most abundant, whereas in frog and fish TBP2 is also
essential for embryogenesis.

TBP family members: specialized or redundant?
The presence of functional TBP paralogs in metazoans
raises the question why more than one TATA binding factor is required in these organisms while only one such
protein is sufficient for proper execution of the transcriptional program in yeast. One plausible hypothesis, supported by global gene expression analysis, is the
requirement of additional components of the basal transcription machinery in order to accommodate a more elaborate gene regulatory framework in these organisms that
is linked to development in metazoans [56]. To accommodate specific developmental roles, one would think that
each of these proteins is involved in transcription of specific subset of genes. However, the relationship between
these initiation factors and regulated genes, as observed in
early Xenopus embryos, is highly complex. On one hand
TBP, TBP2 and TLF are all required for proper development and essential for specific subsets of genes [55,56,85].
On the other hand TBP-ablated embryos can be at least
partially rescued by overexpression of TBP2 suggesting a
significant level of redundancy between the two proteins
[85].
Additionally it has also been observed that different
promoters of the same gene are controlled by different
TBP family members. An example is the tudor gene of
Drosophila, one promoter of which is TBP-responsive
whereas the other is controlled by TRF1 [62]. Similarly,
TLF/TRF2 and TBP work on two different promoters of
the PCNA gene [79]. In addition to these specific examples, other data is also suggestive of more than one TBP
family member working on the same gene. In ChIP-chip
assays in Drosophila S2 cells, it was observed that 20%
of TLF binding sites overlap with TBP binding sites

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[83]. Furthermore, on many genes in early frog embryos
both TBP and TBP2 can be located on same genes by
similar assays [56]. These examples highlight the regulatory complexity in higher organisms.

Switching of TBP family members during
development and differentiation
Another intriguing explanation for the existence of multiple TATA binding factors in metazoans is spatio-temporal control of gene expression where different factors
control gene expression in different tissue types or in
different stages of development [92,93]. The idea is that
when cells differentiate, the expression levels of one
TATA binding factor decrease whereas those of another
increase, effectively switching the gene-regulatory control from one factor to the other. A prime example of
such a switch is the replacement of TBP by TBP2 in
female germ cells (Figure 4). In frog and mouse oocytes
TBP2 is abundant with little if any TBP present [50,86].
As early embryogenesis proceeds TBP levels increase
reaching to their maximum at the time of zygotic gene
activation [49,50]. TBP2 is actively degraded to low
levels during meiotic maturation of oocytes [86]. In
frogs the switching is not complete as low levels of
TBP2 persist for some time and are essential for embryogenesis [56,85]. Interestingly, when TBP is ectopically
expressed in oocytes, it can promote transcription [86],
showing that expression differences can drive initiation
factor switching. This is in contrast to another subset of
specific promoters where the requirements of the specific TATA-related proteins are non-redundant even
when co-expressed, as is the case with strictly TBP2specific promoters in early frog embryos [56]. It should
be noted that early mouse embryos do not tolerate the
overexpression of TBP2 [57], whereas in Xenopus
embryos, which in contrast to mouse embryos require
TBP2, this factor can partially rescue a knockdown of
TBP. Moreover overexpression of TBP2 in the presence
of normal levels of TBP does not interfere with normal
development in this species [85], suggesting a higher
plasticity in core factor usage in Xenopus as compared
to mouse.
In another but more controversial example, the canonical TFIID complex is replaced by a smaller 150 to 200
kDa complex consisting of TBP2/TRF3 and TBP-associated factor 3 (TAF3) when mouse myoblasts differentiate into myotubes in culture [89]. However, muscle
differentiation does not require TBP2 in vivo [57] and
TBP2 expression is not detected outside germ cells and
early embryos by other laboratories. Also, TAF3 is a histone fold (HFD)-containing TAF and it is surprising
that in the TRF3-TAF3 complex no HFD-containing
partner-TAFs have been identified. Using in vitro reconstituted transcription systems, it was shown that a

Page 8 of 12

recombinant TBP2-TAF3 complex could promote transcription from the Myogenin promoter, whereas a TFIID
complex substoichiometric for TAF3 could not [94],
highlighting a role for TAF3 in MyoD-dependent transcriptional activation of Myogenin.

TBP-related factors and germ cell transcription
There is increasing evidence that exquisitely specialized
mechanisms of gene expression operate in germ cells.
These germ cell-specific programs of transcription are
facilitated not only by specialized isoforms of sequencespecific transcription factors but also by variation in the
core transcription machinery. As reviewed in previous
sections female germ cells lack detectable levels of TBP
protein with abundant TBP2, which is essential for their
development. Parallel to TBP2 in oocytes, TLF is essential for sperm development. TBP2 knockout male mice
and TLF-lacking female mice are fertile showing strict
division of labor between the two factors in mammals.
In lower vertebrates, on the contrary, both TLF and
TBP2 are also important for proper embryogenesis as
detailed above.
This germ cell-restricted expression pattern of TBPrelated factors is also accompanied by variations in the
composition and expression of some other key components of core transcription machinery (Figure 5). For
example TFIIA-like factor (ALF) is an exclusively germ
cell-specific isoform of core transcription factor TFIIA
[95]. In fact in frog oocytes ALF completely replaces
TFIIA, a situation that parallels replacement of TBP by
TBP2 [96]. A number of TBP-associated factors have
germ cell-specific isoforms. TAF4b, a paralog of TAF4,
is highly expressed in mouse testis and ovary. It is part
of an ovary-specific form of TFIID which is specifically
found in the granulosa cells but not developing oocytes
[97]. Deletion of TAF4b in knockout mice results in
completely sterile females, and males which become
sterile very early in their life [97-99]. TAF7L is highly
expressed in spermatogonia. However, it remains in the
cytoplasm and only translocates to the nucleus in pachytene cells and haploid spermatids before becoming
silenced in post-meiotic spermatocytes [100]. Similarly
sperm-specific isoforms of TAF4, 5, 6, 8 and 12 have
been reported in Drosophila [101,102].
Presence of highly specialized versions of core transcription machinery components in germ cells raises
this fundamental question why these cells need a different core transcription apparatus. One possibility is that
meiosis requires a specialized environment for transcription. Meiotic cell division is unique to germ cells. The
expression of both TBP2 and TLF is highest and that of
TBP is the lowest during the meiotic phases of germ
cell development. For instance TLF protein is detectable
during early pachytene stages of spermatocytes where it

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Page 9 of 12

Figure 5 Many germ cell-specific variants of general transcription factors (GTFs) have evolved. Only factors are shown for which a role
has been documented. While TBP dominates transcription in somatic cells (A) and is also expressed in testis (C), it is completely replaced by
TBP2 in female germ cells (B). Male germ cells express high levels of TLF and a vital share of transcription in these cells is dependent on this
factor. Similarly TFIIA is replaced completely in oocytes and partially in sperm by ALF. Variants of TFIID contain germ cell-specific TAFs.

is principally cytoplasmic [78]. Later it migrates to the
nucleus and stays there until the shutdown of transcription in elongated spermatids. Similarly, TBP2 is also
abundant during transcriptionally active phases of meiosis in oocytes [50,57,86].
TBP-related factors may support chromatin remodeling
by controlling the expression of key chromatin regulators
at important time points during the gametogenesis. A lack
of TLF results in defective chromocentre formation [78],
whereas the absence of TBP2 in oocytes leads to chromatin disorganization and defects in condensation [57]. Ovaries of TBP2 knockout mice exhibit down regulation of
genes involved in chromatin organization including
oocyte-specific linker histone H1, H1foo, and the DNA
methyltransferase Dnmt1 [57]. Confocal analysis shows
that TLF is associated with both heterochromatin and
euchromatin [78]. These results illustrate the importance
of TLF and TBP2 for chromatin in germ cells.

Perspective: The TBP family as a paradigm in
diversity of the transcription machinery
The transcription initiation machinery in not universal
but variable in composition in higher eukaryotes, which
is mainly on account of duplicated paralog subunits of
the canonical TFIID and TFIIA complexes. The TBP
family presents a prime and well-characterized example
of how non-universal mechanisms of transcription
initiation contribute to cell-specific developmental gene
expression programs. This diversification most likely
serves to expand the gene regulatory potential required
for embryonic development in metazoans (TLF), and
vertebrates in particular (TBP2). Initiation factor

switching occurs on account of differential expression of
these proteins in gametes (TBP2 and TLF), embryos
(TBP, TBP2 and TLF) and somatic cells (transcription
dominated by TBP). Mice however have lost the genetic
requirement for TLF and TBP2 during embryogenesis.
An important goal of future research is to decipher the
molecular mechanisms underlying the specificity of factor-promoter interaction, both at the level of core promoter recognition and at the level of protein-protein
interactions. TBP is known to work in several multisubunit complexes. For other members of the family
this area has not been fully explored. Germ cell and
embryonic gene regulation involve gene regulatory networks that integrate intercellular signaling and epigenetic regulation to reprogram chromatin state and
produce activators and repressors required for pluripotency and induction of lineage commitment. The transcription initiation machinery is adapted to mediate the
versatility required for the transcription program of
germ cell and embryonic development. Elucidation of
the molecular mechanisms underlying the diverse biological roles of the TBP family factors, using classical biochemistry, molecular biology and state-of-the-art
genomics approaches, will provide deeper insight in the
role of transcriptional regulation in pluripotency and
differentiation in higher eukaryotes.
List of abbreviations
ALF: TFIIA-like factor; DPE: downstream promoter element; DRE: DNA
replication element; DREF: DRE-binding factor; Inr: initiator element; NURF:
nucleosome remodeling factor; PCNA: proliferating cell nuclear antigen; PIC:
pre-initiation complex; SL1: selectivity factor 1; SNAPc: snRNA activating
protein complex; TAF: TBP-associated factor; TBP: TATA box binding protein;

Akhtar and Veenstra Cell & Bioscience 2011, 1:23
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TFIIA: transcription factor II A (RNAP-II initiation factor); TFIIB: transcription
factor II B (RNAP-II initiation factor); TFIIIB: transcription factor III B (RNAP-III
initiation factor); TFIID: transcription factor II D (RNAP-II initiation factor); TLF:
TBP-like factor; MBT: mid-blastula transition; TRF: TBP-related factor; RNAP:
RNA polymerase.
Acknowledgements
This work was supported by Higher Education Commission of Pakistan with
a PhD fellowship to WA and by NWO-ALW (Netherlands Organization for
Scientific Research-Research Council for Earth and Life Sciences) with grant
number 864.03.002 to GJVC.
Authors’ contributions
WA wrote the manuscript and made figures. GJCV contributed to the
writing and made figures. Both authors read and approved the final
manuscript.
Competing interests
The authors declare that they have no competing interests.
Received: 27 April 2011 Accepted: 27 June 2011
Published: 27 June 2011
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doi:10.1186/2045-3701-1-23
Cite this article as: Akhtar and Veenstra: TBP-related factors: a paradigm
of diversity in transcription initiation. Cell & Bioscience 2011 1:23.

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