LINT, a Novel dL(3)mbt-Containing Complex, Represses Malignant Brain Tumour Signature Genes

Abstract

Mutations in the l(3)mbt tumour suppressor result in overproliferation of Drosophila larval brains. Recently, the derepression of different gene classes in l(3)mbt mutants was shown to be causal for transformation. However, the molecular mechanisms of dL(3)mbt-mediated gene repression are not understood. Here, we identify LINT, the major dL(3)mbt complex of Drosophila. LINT has three core subunits—dL(3)mbt, dCoREST, and dLint-1—and is expressed in cell lines, embryos, and larval brain. Using genome-wide ChIP–Seq analysis, we show that dLint-1 binds close to the TSS of tumour-relevant target genes. Depletion of the LINT core subunits results in derepression of these genes. By contrast, histone deacetylase, histone methylase, and histone demethylase activities are not required to maintain repression. Our results support a direct role of LINT in the repression of brain tumour-relevant target genes by restricting promoter access.

Chromatin reader L(3)mbt requires the Myb–MuvB/DREAM transcriptional regulatory complex for chromosomal recruitment

“…2B. These data complement conclusions of Meier et al who reported that siRNA depletion of PrSet7 and concomitant loss of genome-wide H4K20 mono-and dimethyl modifications, had no effect on expression of any of the specific loci they focused on, the repression of which is dependent upon L(3)mbt through dLINT (12). melanogaster.…”

“…a large set, rather than one specific type of methylated histone. For example, methylated H4K20 appears to be dispensable for L(3)mbt-mediated repression of some genes (12), and it is possible that other mono-and dimethylated histones may perform this function at specific loci.…”

“…Sex comb in midleg (dSCM) is involved in regulation by repression of homeotic developmental patterning and thus classified as a polycomb gene (9). Akin to dSCM, the available data suggests that l(3)mbt functions through the repression of developmentally regulated genes (10)(11)(12)(13), although the inhibitory mechanism remains an unresolved question. A potential clue into how repression might be exerted comes from biochemical studies by Reinberg and coworkers, stating that the human L(3)mbt can, once bound to DNA, act as a chromatin compaction agent; the bound protein condenses chromatin and thus prevents the expression of the underlying genes (14).…”

“…In further support of this latter notion, a recently identified "LINT" complex was biochemically shown to harbor L(3)mbt, partially colocalize with it, genome-wide, and is required for L(3)mbtmediated repression. In Drosophila, L(3)mbt's ability to function at many sites is independent of the histone H4K20 modification status (12), whereas the contrary has been emphasized for human L3MBTL1 function (17). However, the H4K20 monomethyl mark, set by the histone methyltransferase PRSet7, is stabilized by L(3)mbt binding in a process that is likely important for proper chromatin organization (24).…”

Chromatin regulation: How complex does it get?

“…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.…”