Chromatin Repressive Complexes in Stem Cells, Development, and Cancer

Abstract

The chromatin environment is essential for the correct specification and preservation of cell identity through modulation and maintenance of transcription patterns. Many chromatin regulators are required for development, stem cell maintenance, and differentiation. Here, we review the roles of the polycomb repressive complexes, PRC1 and PRC2, and the HDAC1- and HDAC2-containing complexes, NuRD, Sin3, and CoREST, in stem cells, development, and cancer, as well as the ongoing efforts to develop therapies targeting these complexes in human cancer. Furthermore, we discuss the role of repressive complexes in modulating thresholds for gene activation and their importance for specification and maintenance of cell fate.

Transcriptional Control by the SMADs

“…CDKN2B is repressed and methylated in the absence of signal by a complex comprising the corepressor complex CoREST (Laugesen and Helin 2014), together with the oncoprotein ZNF217 and the DNA methylase DNMT3A. TGF-b triggers active DNA demethylation in a process that depends on loss of ZNF217/CoREST/DNMT3A and recruitment of SMAD2/3, the HAT CBP, and the DNA glycosylase TDG with the deaminase, AID.…”

Erratum: A positive role for polycomb in transcriptional regulation via H4K20me1

“…These observations were further confirmed in E(z) 731 mutant clones, where H3K27me3 levels and the expression of Sens were reduced, whereas the expression of Ubx was increased ( Figure 2G-2H' and Supplementary information, Figure S2E-S2E'). Furthermore, dramatic reduction in both the H3K27me3 levels and Sens expression was observed in clones of Su(z)12 4 ( Figure 2I-2J' and Supplementary information, Figure S2F-S2F'), a gene essential for the histone methyltransferase activity of E(z) in catalyzing H3K27me3 [41][42][43]. These results together suggest that Pc positively regulates transcription of Sens by recognizing H3K27me3 modification catalyzed by the intact PRC2.…”

“…AP4, AP4GFP, Hh-Gal4 and AG4 have been described (flybase). Pc XT109 , E(z) 731 and Su(z)12 4 are gifts from Dr Rongwen Xi at NIBS [71]. PR-Set7 EY04668 (B15761), uas-dsRNA Pc (32443R-4), uas-dsRNA E(z) (6502R-4), uas-dsRNA PR-Set7 (3307R-1), uas-dsRNA Br (V38526) and Act5c-Gal4 (B4414) were obtained from Bloomington, NIG or VDRC.…”

“…In order to generate large clones, the Minute technique was applied [72]. With this method, suitable Pc XT109 , E(z) 731 , Su(z)12 4 and PRSet7 EY04668 clones were generated to analyze the expression levels of the indicated genes.…”

Control of adult intestinal identity by the Polycomb repressive machinery

“…The major mechanism by which cells can "lock" defined repressed states and at the same time maintain transcriptional plasticity comes from the Polycomb machinery. [1][2] Discovered almost 30 years ago in Drosophila melanogaster, the Polycomb group of proteins (PcG) maintains transcriptional repression by modifying histone tails to promote chromatin compaction. Polycomb proteins assemble in 2 large multi-protein complexes: the Polycomb repressive complex 1 (PRC1) and 2 (PRC2).…”