A TAF4 coactivator function for E proteins that involves enhanced TFIID binding

Abstract

The multisubunit TFIID plays a direct role in transcription initiation by binding to core promoter elements and directing preinitiation complex assembly. Although TFIID may also function as a coactivator through direct interactions with promoter-bound activators, mechanistic aspects of this poorly defined function remain unclear. Here, biochemical studies show a direct TFIID-E-protein interaction that (1) is mediated through interaction of a novel E-protein activation domain (activation domain 3 [AD3]) with the TAF homology (TAFH) domain of TAF4, (2) is critical for activation of a natural target gene by an E protein, and (3) mechanistically acts by enhancing TFIID binding to the core promoter. Complementary assays establish a gene-specific role for the TAFH domain in TFIID recruitment and activation of a large subset of genes in vivo. These results firmly establish TAF4 as a bona fide E-protein coactivator as well as a mechanism involving facilitated TFIID binding through direct interaction with an E-protein activation domain.

E2a Is Necessary for Smad2/3-Dependent Transcription and the Direct Repression of lefty during Gastrulation

“…While E2a is well known as a transcriptional activator in hematopoiesis (Bradney et al, 2003, Kee, 2009; Chen et al, 2013), two lines of evidence prompted us to investigate whether it was also acting as an activator in the early embryo. First, many well-known Nodal target genes are downregulated in the absence of E2a, but retain Smad2/3 binding (Figure 1 and Table 1).…”

“…In B cell development, E2a can act as either a transcriptional activator or repressor through its association with coactivators and corepressors or by forming homodimers and heterodimer in association with other class I or class II bHLH proteins, which can be repressors or activators (reviewed in (Kee, 2009)). E2a can also associate with transcriptional coactivators such as p300, CBP and TAF4 through one of two AD transactivation domains (Bayly et al, 2004; Bradney et al, 2003; Chen et al, 2013), or with the ETO/MTG class of corepressors through the AD2 and DES domains (Gow et al, 2014; Guo et al, 2009; Zhang et al, 2004). E2a can therefore have potentially widespread effects on transcriptional regulation across the genome, although the effects of E2a loss of function on global transcription patterns have not been investigated.…”

Molecular functions of the transcription factors E2A and E2-2 in controlling germinal center B cell and plasma cell development

“…Moreover, few repressed target genes were highly regulated by the two E-proteins in contrast to a large proportion of the activated target genes. In support of transcriptional activation, E-proteins contain 3 activation domains (AD1, AD2, and AD3), which interact with the coactivators p300 and CBP (Bradney et al, 2003;Bayly et al, 2004) and the promoter recognition factor TFI ID (Chen et al, 2013). At the chromatin level, we identified a novel role for E-proteins in shaping the enhancer landscape at its activated target genes, as E2A and E2-2 are responsible for the induction and maintenance of DHS sites containing E2A-binding sites.…”

“…Within the lymphoid system, E-proteins function as homodimers or heterodimers with a different E-protein (Bain et al, 1993;Shen and Kadesch, 1995). E-proteins are thought to mainly function as transcriptional activators, as they interact with the co-activators p300 and CBP (Bradney et al, 2003;Bayly et al, 2004), as well as the promoter recognition factor TFI ID (Chen et al, 2013). The activity of E-proteins is controlled by the inhibitor of DNA binding proteins, which are HLH proteins lacking the basic DNA-binding domain, and are thus capable of sequestering E-proteins into DNA-bindingincompetent heterodimers (Kee, 2009).…”

SETD6 controls the expression of estrogen-responsive genes and proliferation of breast carcinoma cells

“…Essentially, transcription is regulated by the binding of TBP to the TATA box and the nucleation of TAFs around TBP and the assembly of the pre-initiation complex (PIC), which is composed of RNA polymerase II and the general transcription factors TFIIA, TFIIB, TFIID, TFIIE, TFIIF, and TFIIH. TAF4 principal function appears to mediate interactions between TFIID and transcriptional activators such as SP1, CREB1, retinoic acid receptors, JUN, and basic helix-loop-helix E proteins family, which binds E boxes (CANNTG) 43 . Alternative splice variants of TAF4 lack parts of the TAF homology domain, which mediates association with a variety of transcriptional factors.…”