Chromatin regulation: how complex does it get?

Abstract

Gene transcription is tightly regulated at different levels to ensure that the transcriptome of the cell is appropriate for developmental stage and cell type. The chromatin state in which a gene is embedded determines its expression level to a large extent. Activation or repression of transcription is typically accomplished by the recruitment of chromatin-associated multisubunit protein complexes that combine several molecular tools, such as histone-binding and chromatin-modifying activities. Recent biochemical purifications of such complexes have revealed a substantial diversity. On the one hand, complexes that were thought to be unique have been revealed to be part of large complex families. On the other hand, protein subunits that were thought to only exist in separate complexes have been shown to coexist in novel assemblies. In this review we discuss our current knowledge of repressor complexes that contain MBT domain proteins and/or the CoREST co-repressor and use them as a paradigm to illustrate the unexpected heterogeneity and tool sharing of chromatin regulating protein complexes. These recent insights also challenge the ways we define and think about protein complexes in general.

Keywords: ATP, adenosine triphosphate; BAP, brahma associated protein; BHC80, BRAF-histone deacetylase complex 80; BRG1, brahma Related Gene 1; CHD, chromo domain helicase DNA binding; CoREST; CoREST REST, corepressor; DNA, deoxyribonucleic acid; DNMT, DNA methyltransferase; DP-1, dimerization partner 1; E2F, E2 transcription Factor; ELM2, EGL-27 and MTA1 homology 2; ES cell, embryonic stem cells; H, histone; HDAC, histone deacetylas; HMTase, histone methylase; HP1, heterochromatin protein 1; K, lysine; L3MBTL, lethal 3 malignant brain tumor-like; LINT, l(3)mbt interacting; LSD1, lysine-specific demethylase 1; Lint-1, l(3)mbt interacting 1; MBT protein; MBT, malignant brain tumor; MBTS, malignant brain tumor signature; NPA1, nucleosome assembly protein; NRSF, neural-restrictive silencing factor; NuRD, nucleosome remodeling and deacetylase; PBAP, polybromo-associated BAP; PHD, plant homeo domain; PRC1, polycomb repressive complex 1; PRE, polycomb responsive element; Pc, polycomb; PcG, polycomb group; Ph, polyhomeotic; Pho, pleiohomeotic; PhoRC, Pho repressive complex; Psc, posterior sex combs; RB, retinoblastoma; REST, repressor element 1 silencing transcription factor; RNA, ribonucleic acid; Rpd3, reduced potassium dependency 3; SANT, SWI/ADA2/N-CoR/TFIIIB; SCML, sex combs on midleg-like; SLC, SFMBT1, LSD1, CoREST; SWH, Salvador-Warts-Hippo; SWI/SNF, switching defective/sucrose non-fermenting; Sce, sex combs extra; Scm, sex combs on midleg; Sfmbt, Scm-related gene containing 4 mbt domains; TSS, transcription start site; YY1, ying-yang 1; ZNF, zinc finger; complex family; dL(3)mbt, Drosophila Lethal 3 malignant brain tumor; hBRM, human Brahma; l(3)mbt, lethal 3 malignant brain tumor; protein complex; transcriptional regulation.

Figure 1.

Evolution of a protein complex family. Schematic representation of a monomorphic complex (Complex A) that evolves into a family of polymorphic complexes (Complexes A1, A2 and A3).

Figure 2.

Complex families: developmentally regulated cell type-specific expression versus coexistence in the same cell. Scheme illustrating different modes of expression of protein complex family members. Left: Not all members of a protein complex family coexist. Expression of certain subunits is developmentally regulated. As a consequence certain complex family members are only present at particular developmental stages (e.g., SWI/SNF complexes; see text for details). Right: Complex family members coexisting in the same cell type (e.g., PRC1 complexes, see text for details).

Figure 3.

Merging protein complex families. Simplified model of how boundaries between 2 different classes of protein complex families break down as scientific progress (arrow from top to bottom) leads to the identification of novel assemblies. Initially, complex families are defined by the presence of signature subunits (depicted in green/orange or blue/yellow; e.g., MBT domain proteins and CoREST, see text for details). Complex families expand as more complexes are being identified. Some accessory subunits (red) are being found in complexes from both families but the presence of signature subunits still allows an unambiguous classification of complexes. Eventually, complexes are being identified which combine signature subunits from different families. The complex families have merged.