SFMBT1 functions with LSD1 to regulate expression of canonical histone genes and chromatin-related factors

Abstract

SFMBT1 (Scm [Sex comb on midleg] with four MBT [malignant brain tumor] domains 1) is a poorly characterized mammalian MBT domain-containing protein homologous to Drosophila SFMBT, a Polycomb group protein involved in epigenetic regulation of gene expression. Here, we show that SFMBT1 regulates transcription in somatic cells and during spermatogenesis through the formation of a stable complex with LSD1 and CoREST. When bound to its gene targets, SFMBT1 recruits its associated proteins and causes chromatin compaction and transcriptional repression. SFMBT1, LSD1, and CoREST share a large fraction of target genes, including those encoding replication-dependent histones. Simultaneous occupancy of histone genes by SFMBT1, LSD1, and CoREST is regulated during the cell cycle and correlates with the loss of RNA polymerase II at these promoters during G2, M, and G1. The interplay between the repressive SFMBT1-LSD1-CoREST complex and RNA polymerase II contributes to the timely transcriptional regulation of histone genes in human cells. SFMBT1, LSD1, and CoREST also form a stable complex in germ cells, and their chromatin binding activity is regulated during spermatogenesis.

Chromatin regulation: How complex does it get?

“…14,15 Moreover, expression of recombinant full-length SFMBT1 or its MBT domains in cell lines reduces chromatin accessibility to nuclease digestion. 23 As we will detail below, MBT domain proteins are found in several multisubunit protein complexes (see Table 1 for a list of MBT and CoREST complexes discussed in this review). They provide these complexes with a tool (the MBT domains) for binding to mono-and di-methylated nucleosomes and for establishing repressive chromatin structures, potentially by way of nucleosome compaction.…”

“…However, recent studies in human and Drosophila have identified novel assemblies that combine MBT and CoREST proteins [20][21][22][23] (Table 1). Human SFMBT1 was isolated in a complex with LSD1 and CoREST (SLC complex) and the remaining subunits of known CoREST complexes.…”

“…24 SLC complex subunits are stably associated in both human cells, as well as mouse testes, where SFMBT1 expression levels are highest compared to other tissues. 23 The recently identified Drosophila LINT complex also combines MBT and CoREST proteins. LINT has 3 core subunits: dL(3)mbt, dLint-1 (Drosophila L(3)mbt interacting protein-1), and dCoREST and is expressed in cell lines, embryos and larval brain.…”

“…20,23 Roughly one third of SLC bound targets, are enriched for genes with a function in chromatin and nucleosome assembly, among them replicationdependent histone gene clusters. 23 The latter constitute multiple gene copies encoding canonical histones that need to be transcribed efficiently during S-phase.…”

“…20,23 Roughly one third of SLC bound targets, are enriched for genes with a function in chromatin and nucleosome assembly, among them replicationdependent histone gene clusters. 23 The latter constitute multiple gene copies encoding canonical histones that need to be transcribed efficiently during S-phase. 83,84 Interestingly, the occupancy of SLC complex at histone genes appeared to be cell cycle dependent and an enrichment of RNA polymerase II at the promoters during S-phase was accompanied by a loss of all 3 SLC complex components.…”