Histone H4 lysine 20 monomethylation promotes transcriptional repression by L3MBTL1

Abstract

Lethal 3 malignant brain tumor 1 (L3MBTL1), a homolog of the Drosophila polycomb tumor suppressor l(3)mbt, contains three tandem MBT repeats (3xMBT) that are critical for transcriptional repression. We recently reported that the 3xMBT repeats interact with mono-and dimethylated lysines in the amino termini of histones H4 and H1b to promote methylation-dependent chromatin compaction. Using a series of histone peptides, we now show that the recognition of mono-and dimethylated lysines in histones H3, H4 and H1.4 (but not their trimethylated or unmodified counterparts) by 3xMBT occurs in the context of a basic environment, requiring a conserved aspartic acid (D355) in the second MBT repeat. Despite the broad range of in vitro binding, the chromatin association of L3MBTL1 mirrors the progressive accumulation of H4K20 monomethylation during the cell cycle. Furthermore, transcriptional repression by L3MBTL1 is enhanced by the H4K20 monomethyltransferase PR-SET7 (to which it binds) but not SUV420H1 (an H4K20 trimethylase) or G9a (an H3K9 dimethylase) and knockdown of PR-SET7 decreases H4K20me1 levels and the chromatin association of L3MBTL1. Our studies identify the importance of H4K20 monomethylation and of PR-SET7 for L3MBTL1 function.

L3MBTL1 polycomb protein, a candidate tumor suppressor in del(20q12) myeloid disorders, is essential for genome stability

“…This compaction requires that the nucleosome contain a mono-or dimethylated lysine 26 on histone H1b or lysine 20 on histone H4 (H4K20) (7). L3MBTL1 binds to chromatin most prominently during the S phase of the cell cycle, concomitant with the appearance of the monomethylated H4K20 (H4K20me1) mark (8), suggesting that the biological function of L3MBTL1 may be related to DNA replication.…”

“…We previously demonstrated that L3MBTL1 functions as an HDAC-independent transcriptional repressor (6) that binds preferentially to mono-and dimethylated lysines of histones via the second of its three MBT repeats (7,8). The three MBT domains of L3MBTL1 are sufficient to compact nucleosomal arrays.…”

Dynamic regulation of the PR-Set7 histone methyltransferase is required for normal cell cycle progression

“…Subsequent studies demonstrated that PR-Set7-mediated H4K20me1 is required for chromatin compaction and transcriptional repression of specific genes, including some involved in mammalian differentiation (Biron et al 2004;Trojer et al 2007; Kalakonda et al 2008;Sims and Rice 2008). Recent studies indicate that PR-Set7 also plays an essential role in mammalian cell cycle progression (Karachentsev et al 2005;Jorgensen et al 2007;Tardat et al 2007;Houston et al 2008;Huen et al 2008;Yin et al 2008).…”

Targeting the epigenome in malignant pleural mesothelioma

“…In a series of elegant experiments, LaFave et al (92) observed that BAP1 mutations, which typically result in loss of protein expression, increased EZH2 as well as SUZ12 expression in MPM cells. Up-regulation of EZH2 in BAP1 mutant cells was associated with reduced levels of H4K2Me1, as well as decreased occupancy of L3MBTL2 (an atypical polycomb protein which recognizes this repressive histone mark) within the EZH2 promoter (96,97). Additional experiments demonstrated that BAP1 deubiquitinates and thereby stabilizes and co-localizes with L3MBTL2 within the EZH2 promoter.…”