TIF1γ Controls Erythroid Cell Fate by Regulating Transcription Elongation

Abstract

Summary Recent genome-wide studies have demonstrated pausing of RNA polymerase II (Pol II) occurred on many vertebrate genes. By genetic studies in the zebrafish tif1γ mutant moonshine we found that loss of function of Pol II-associated factors PAF or DSIF rescued erythroid gene transcription in tif1γ-deficient animals. Biochemical analysis established physical interactions among TIF1γ, the blood-specific SCL transcription complex, and the positive elongation factors p-TEFb and FACT. ChIP assays in human CD34+ cells supported a TIF1γ-dependent recruitment of positive elongation factors to erythroid genes to promote transcription elongation by counteracting Pol II pausing. Our study establishes a mechanism for regulating tissue cell fate and differentiation through transcription elongation.

The bromodomain interaction module

“…The BRD of ATAD2 has been shown to immunoprecipitate histone H3 (K14 ac [68]) but this interaction has not been quantified yet, while the closely homologous KIAA1240 binds to histone H4 (K5 ac [33,69] [70]). Subfamily V of the human BRDs contains the transcriptional repressor tripartite motif-containing 66 (TRIM66) [71], the tripartite motif-containing 33 (TRIM33) [72], the transcriptional regulator transcriptional intermediary factor 1 (TIF1a) [73], the transcriptional regulators nuclear auto-antigen Sp-100 (SP100) [74], nuclear autoantigen Sp-110 (SP110) [75] and SP140 nuclear body protein (SP140) [76] as well as the SP140-like protein (LOC93349), the transcriptional repressor bromodomain adjacent to zinc finger domain 2A (BAZ2A) [77] and the bromodomain adjacent to zinc finger domain 2B (BAZ2B) [78]. The main characteristic of this sub-class of bromodomains is the existence of a PHD/BRD tandem module which seems to be a necessary structural motif for peptide recognition as well as protein stability [73,79].…”

Serine-7 but not serine-5 phosphorylation primes RNA polymerase II CTD for P-TEFb recognition

“…In addition, Ser7 of the CTD can also be phosphorylated, which has been linked to small nuclear RNAs (snRNA) transcription and recruitment of the integrator complex [9][10][11][12][13] . Whereas some genes, for example, those on CpG islands, can directly proceed to the elongation state by recruiting P-TEFb to RNAPII 14 , genomewide studies suggest that the majority of genes in higher eukaryotes are under the control of promoter-proximal pausing [15][16][17] .…”

Transcription cofactors TRIM24, TRIM28, and TRIM33 associate to form regulatory complexes that suppress murine hepatocellular carcinoma

“…TRIM33 acts on the TGF-β pathway either as a monoubiquitin ligase for SMAD4 and/or as a cofactor for phosphorylated SMAD2/3 (17, 32), whereas it is also reported to act directly on the transcription initiation complex by promoting recruitment of positive transcription elongation factor b and the facilitates chromatin transcription (FACT) complex to counteract RNA polymerase II pausing (33).…”