Keeping things quiet: roles of NuRD and Sin3 co-repressor complexes during mammalian development

Abstract

Gene inactivation studies of mammalian histone and DNA-modifying proteins have demonstrated a role for many such proteins in embryonic development. Post-implantation embryonic lethality implies a role for epigenetic factors in differentiation and in development of specific lineages or tissues. However a handful of chromatin-modifying enzymes have been found to be required in pre- or peri-implantation embryos. This is significant as implantation is the time when inner cell mass cells of the blastocyst exit pluripotency and begin to commit to form the various lineages that will eventually form the adult animal. These observations indicate a critical role for chromatin-modifying proteins in the earliest lineage decisions of mammalian development, and/or in the formation of the first embryonic cell types. Recent work has shown that the two major class I histone deacetylase-containing co-repressor complexes, the NuRD and Sin3 complexes, are both required at peri-implantation stages of mouse development, demonstrating the importance of histone deacetylation in cell fate decisions. Over the past 10 years both genetic and biochemical studies have revealed surprisingly divergent roles for these two co-repressors in mammalian cells. In this review we will summarise the evidence that the two major class I histone deacetylase complexes in mammalian cells, the NuRD and Sin3 complexes, play important roles in distinct aspects of embryonic development.

Fig. 1

(A) Schematic of the NuRD and Sin3 co-repressor multiprotein complexes in mammalian cells. The individual components of the complexes are indicated above, with arrows indicating associations with transcriptional repressors. Each complex contains both Hdac1 and Hdac2 proteins and both Rbbp4 and Rbbp7 proteins. NuRD may contain both Gatad2a and Gatad2b, but Mta1, Mta2 and Mta3 are mutually exclusive within NuRD, as are Mbd2 or Mbd3. Similarly Sin3 complexes contain either Sin3a or Sin3b. Ikaros and Aiolos have been reported to associate with both complexes. “Dnmts” refers to reports that some NuRD components can interact with Dnmt1, Dnmt3a and Dnmt3b. (B) The co-repressor Sin3 serves as a scaffold, physically coupling class I histone deacetylases (via the Hdac-interaction domain, red) to sequence-specific transcriptional repressors (via PAH domains, green). In this way Sin3 can be recruited to diverse promoter sequences in many different cell types. The specificity and functionality of the complex are further increased by incorporating adaptor proteins that can recruit additional repressors and chromatin-modifying complexes. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)