Regulation of transcription by the MLL2 complex and MLL complex–associated AKAP95

Jiang, Hao; Lu, Xiangdong; Shimada, Miho; Dou, Yali; Tang, Zhanyun; Roeder, Robert G.

doi:10.1038/nsmb.2656

Cited by 54 publications

(75 citation statements)

References 48 publications

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“…Direct and causal functions of several KMT2s in transcription initiation have been elegantly demonstrated in vitro 57,59,82 , and are further supported by KMT2-dependent RNAPII binding at promoters and enhancers in various cells. 48,68 The function of H3K4me3 in transcription has been extensively discussed.…”

Section: Physiological Functions Of Kmt2 Family Histone Methyltransfementioning

confidence: 88%

Hijacked in cancer: the KMT2 (MLL) family of methyltransferases

2015

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Preface Lysine methyltransferase 2 family (KMT2) proteins methylate lysine 4 on the histone H3 tail at important regulatory regions in the genome and thus impart critical functions through modulating chromatin structures and DNA accessibility. While the human KMT2 family was initially named the mixed lineage leukemia (MLL) family, due to the role of the founding member KMT2A (also called MLL, MLL1, ALL-1, HRX) in this disease, recent exome-sequencing studies revealed KMT2 genes to be among the most frequently mutated genes in many types of human cancers. Efforts to integrate the molecular mechanisms of KMT2 with its roles in tumorigenesis have led to the development of first-generation inhibitors of KMT2 function, which could become novel cancer therapies.

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Section: Physiological Functions Of Kmt2 Family Histone Methyltransfementioning

confidence: 88%

Hijacked in cancer: the KMT2 (MLL) family of methyltransferases

2015

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“…It is interesting, however, that HDAC3 is a direct AKAP95 binding protein [45] and, because HDAC3 is responsible for the de-acetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4) leading to gene repression, one could hypothesise that AKAP95, through its DNA-binding features, recruits HDAC3 to ribosomal chromatin and subsequently represses rRNA production. Another possible epigenetic molecular mechanism could be mediated through a functional association with mixed-lineage leukemia (MLL) complexes and enhanced methyltransferase activity, suggesting a role for AKAP95 in regulating histone methylation and gene expression [47]. MLL2 is involved in a broad range of cellular processes.…”

Section: Discussionmentioning

confidence: 99%

A‐kinase anchoring protein AKAP95 is a novel regulator of ribosomal RNA synthesis

et al. 2016

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The RNA polymerase I transcription apparatus acquires and integrates the combined information from multiple cellular signalling cascades to regulate ribosome production essential for cell growth and proliferation. In the present study, we show that a subpopulation of A-kinase anchoring protein 95 (AKAP95) targets the nucleolus during interphase and is involved in regulating rRNA production. We show that AKAP95 co-localizes with the nucleolar upstream binding factor, an essential rRNA transcription factor. Similar to other members of the C 2 H 2 -zinc finger family, we show, using systematic selection and evolution of ligands by exponential enrichment and in vitro binding analysis, that AKAP95 has a preference for GC-rich DNA in vitro, whereas fluorescence recovery after photobleaching analysis reveals AKAP95 to be a highly mobile protein that exhibits RNA polymerase I and II dependent nucleolar trafficking. In line with its GC-binding features, chromatin immunoprecipitation analysis revealed AKAP95 to be associated with ribosomal chromatin in vivo. Manipulation of AKAP95-expression in U2OS cells revealed a reciprocal relationship between the expression of AKAP95 and 47S rRNA. Taken together, our data indicate that AKAP95 is a novel nucleolus-associated protein with a regulatory role on rRNA production.

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“…Components of the Trr and Trx HMTs, or their mammalian homologues MLL1-4, are required for the normal expression of some eukaryotic genes, presumably because H3K4 methylation, which is recognized by a structural motif (PHD) found in several proteins associated with histone modification and transcription, recruits proteins that promote transcriptional activation. Moreover, recent biochemical studies established that H3K4 methylation could promote transcription in in vitro assays (Jiang et al, 2013). …”

Section: Introductionmentioning

confidence: 99%

Yorkie Promotes Transcription by Recruiting a Histone Methyltransferase Complex

Slattery

et al. 2014

Cell Reports

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SUMMARY Hippo signaling limits organ growth by inhibiting the transcriptional coactivator Yorkie. Despite the key role of Yorkie in both normal and oncogenic growth, the mechanism by which it activates transcription has not been defined. We report that Yorkie binding to chromatin correlates with histone H3K4 methylation, and is sufficient to locally increase it. We show that Yorkie can recruit a histone methyltransferase complex, through binding between WW domains of Yorkie and PPxY sequence motifs of NcoA6, a subunit of the Trithorax-related (Trr) methyltransferase complex. Cell culture and in vivo assays establish that this recruitment of NcoA6 contributes to Yorkie’s ability to activate transcription. Mammalian NcoA6, a subunit of Trr-homologous methyltransferase complexes, can similarly interact with Yorkie’s mammalian homologue YAP. Our results implicate direct recruitment of a histone methyltransferase complex as central to transcriptional activation by Yorkie, linking the control of cell proliferation by Hippo signaling to chromatin modification.

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Regulation of transcription by the MLL2 complex and MLL complex–associated AKAP95

Cited by 54 publications

References 48 publications

Hijacked in cancer: the KMT2 (MLL) family of methyltransferases

Hijacked in cancer: the KMT2 (MLL) family of methyltransferases

A‐kinase anchoring protein AKAP95 is a novel regulator of ribosomal RNA synthesis

Yorkie Promotes Transcription by Recruiting a Histone Methyltransferase Complex

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