The complex activities of the SET1/MLL complex core subunits in development and disease

Jiang, Hao

doi:10.1016/j.bbagrm.2020.194560

Cited by 42 publications

(46 citation statements)

References 156 publications

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“…Also notable were transcription regulators (DPY30, MESP1, POU4F1, HOXC8, FOXK2, HOXC10, DLX5, E2F6, and SP8 [ q < 0.05]). DPY30 (Dpy-30 Histone Methyltransferase Complex Regulatory Subunit) ( q = 0.0109) is a core subunit of the SET1/MLL family of H3K4 methyltransferases that directly controls cell cycle regulators [ 30 ].…”

Section: Resultsmentioning

confidence: 99%

Survival-Critical Genes Associated with Copy Number Alterations in Lung Adenocarcinoma

Rao

Farooqui

et al. 2021

Cancers

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Chromosome Instability (CIN) in tumors affects carcinogenesis, drug resistance, and recurrence/prognosis. Thus, it has a high impact on outcomes in clinic. However, how CIN occurs in human tumors remains elusive. Although cells with CIN (i.e., pre/early cancer cells) are proposed to be removed by apoptosis and/or a surveillance mechanism, this surveillance mechanism is poorly understood. Here we employed a novel data-mining strategy (Gene Expression to Copy Number Alterations [CNA]; “GE-CNA”) to comprehensively identify 1578 genes that associate with CIN, indicated by genomic CNA as its surrogate marker, in human lung adenocarcinoma. We found that (a) amplification/insertion CNA is facilitated by over-expressions of DNA replication stressor and suppressed by a broad range of immune cells (T-, B-, NK-cells, leukocytes), and (b) deletion CNA is facilitated by over-expressions of mitotic regulator genes and suppressed predominantly by leukocytes guided by leukocyte extravasation signaling. Among the 39 CNA- and survival-associated genes, the purine metabolism (PPAT, PAICS), immune-regulating CD4-LCK-MEC2C and CCL14-CCR1 axes, and ALOX5 emerged as survival-critical pathways. These findings revealed a broad role of the immune system in suppressing CIN/CNA and cancer development in lung, and identified components representing potential targets for future chemotherapy, chemoprevention, and immunomodulation approaches for lung adenocarcinoma.

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Section: Resultsmentioning

confidence: 99%

Survival-Critical Genes Associated with Copy Number Alterations in Lung Adenocarcinoma

Rao

Farooqui

et al. 2021

Cancers

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“…While PRC2 catalyzes H3 K27 methylation leading to transcriptional repression, 43 SET1/MLL histone methyltransferases are generally associated with transcriptional activation via methylation of histone H3 at position K4. 44,45 The reduced interaction of H1.2 K17Ac with subunits of these complexes suggests again a role of H1.2 Ac in modulating their activity, even though the opposite down-stream effects clearly warrant future investigations.…”

Section: Analysis Of Acetylation-specific H1 Interactionsmentioning

confidence: 98%

The interactome of site-specifically acetylated linker histone H1

Hoellmueller

Greiner

Kienle

et al. 2021

Preprint

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Linker histone H1 plays a key role in chromatin organization and maintenance, yet our knowledge of the regulation of H1 functions by posttranslational modifications (PTMs) is rather limited. In this study, we report on the generation of site-specifically mono- and di-acetylated linker histone H1.2 by genetic code expansion. We used these modified histones to identify and characterize the acetylation-dependent cellular interactome of H1.2 by affinity purification-mass spectrometry (AP-MS) and show that site-specific acetylation results in overlapping, but distinct groups of interacting partners. Among these, we find multiple translational initiation factors and transcriptional regulators such as the NAD+-dependent deacetylase SIRT1, which we demonstrate to act on acetylated H1.2. Taken together our data suggests that site-specific acetylation of H1.2 plays a role in modulating protein-protein interactions.

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“…Histone modifications/chromatin remodeling KMT2 family proteins and complexes-The KMT2 family proteins include KMT2A/ MLL1/MLL, KMT2B/MLL2 (also known as MLL4), KMT2C/MLL3, KMT2D/MLL4 (also known as MLL2), KMT2E/MLL5, KMT2F/SET1A, and KMT2G/SET1B. With the exception of MLL5, they are the major H3K4 methyltransferases in mammals by individually acting as the catalytic subunit of the SET1/MLL complexes, which also contain all of WDR5, RBBP5, ASH2L, and DPY30 as the common core subunits that are important for the catalytic activity of the complexes [115,116]. In general, SET1A is responsible for the bulk H3K4me3 at promoters, and MLL1 and MLL2 catalyze promoter H3K4me3 at regulated developmental stages, whereas MLL3 and MLL4 mainly catalyze H3K4me1 at gene enhancers [117].…”

Section: Dna Modificationsmentioning

confidence: 99%

“…In general, SET1A is responsible for the bulk H3K4me3 at promoters, and MLL1 and MLL2 catalyze promoter H3K4me3 at regulated developmental stages, whereas MLL3 and MLL4 mainly catalyze H3K4me1 at gene enhancers [117]. It is worth mentioning that these proteins have physiologically relevant activities independent of H3K4 methylation [116]. Many of these complex components are known to play important roles in HSPC function, and are extensively associated with human cancers [116,118].…”

Section: Dna Modificationsmentioning

confidence: 99%

“…It is worth mentioning that these proteins have physiologically relevant activities independent of H3K4 methylation [116]. Many of these complex components are known to play important roles in HSPC function, and are extensively associated with human cancers [116,118]. KMT2A/MLL1/MLL: MLL1 plays a critical role in normal hematopoiesis and hematologic malignancy [119,120].…”

Section: Dna Modificationsmentioning

confidence: 99%

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A chromatin perspective on metabolic and genotoxic impacts on hematopoietic stem and progenitor cells

Yang

Jiang

2020

Cell. Mol. Life Sci.

Self Cite

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The fate determination in self-renewal and differentiation of hematopoietic stem and progenitor cells (HSCs and HPCs) is ultimately controlled by gene expression, which is profoundly influenced by the global and local chromatin state. Cellular metabolism directly influences the chromatin state through the dynamic regulation of the enzymatic activities that modify DNA and histones, but also generates genotoxic metabolites that can damage DNA and thus pose threat to the genome integrity. On the other hand, mechanisms modulating the chromatin state impact metabolism by regulating the expression and activities of key metabolic enzymes. Moreover, through regulating either DNA damage response directly or expression of genes involved in this process, chromatin modulators play active and crucial roles in guarding the genome integrity, breaching of which result in defective HSPC function. Therefore, HSPC function is regulated by the dynamic and two-way interactions between metabolism and chromatin. Here, we review recent advances that provide a chromatin perspective on the major impacts the metabolic and genotoxic factors can have on HSPC function and fate determination.

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The complex activities of the SET1/MLL complex core subunits in development and disease

Cited by 42 publications

References 156 publications

Survival-Critical Genes Associated with Copy Number Alterations in Lung Adenocarcinoma

Survival-Critical Genes Associated with Copy Number Alterations in Lung Adenocarcinoma

The interactome of site-specifically acetylated linker histone H1

A chromatin perspective on metabolic and genotoxic impacts on hematopoietic stem and progenitor cells

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