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Myeloma-specific superenhancers affect genes of biological and clinical relevance in myeloma.

ABSTRACT: Multiple myeloma (MM) is an aggressive plasma cell neoplasm characterized by genomic heterogeneity. Superenhancers (SEs) are defined as large clusters of enhancers in close genomic proximity, which regulate genes for maintaining cellular identity and promote oncogenic transcription to which cancer cells highly addicted. Here, we analyzed cis-regulatory elements in MM samples with H3K27ac ChIP-seq, to identify novel SE-associated genes involved in the myeloma pathogenesis. SEs and their associated genes in cancerous tissue were compared with the control samples, and we found SE analysis alone uncovered cell-lineage-specific transcription factors and well-known oncogenes ST3GAL6 and ADM. Using a transcriptional CDK7 inhibitor, THZ1, coupled with H3K27ac ChlP-seq, we identified MAGI2 as a novel SE-associated gene of myeloma cells. Elevated MAGI2 was related to myelomagenesis with gradual increased expression from MGUS, SMM to newly diagnosed and relapsed MM. High prevalence of MAGI2 was also associated with poor survival of MM patients. Importantly, inhibition of the SE activity associated with MAGI2 decreased MAGI2 expression, inhibited cell growth and induced cell apoptosis. Mechanistically, we revealed that the oncogenic transcription factor, MAF, directly bound to the SE region and activated gene transcription. In summary, the discoveries of these acquired SEs-associated genes and the novel mechanism by which they are regulated provide new insights into MM biology and MAGI2-MAF-SE regulatory circuit offer potential novel targets for disease treatment.

SUBMITTER: Jia Y

PROVIDER: S-EPMC7881003 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Myeloma-specific superenhancers affect genes of biological and clinical relevance in myeloma.

Jia Yunlu Y Zhou Jianbiao J Tan Tze King TK Chung Tae-Hoon TH Wong Regina Wan Ju RWJ Chooi Jing-Yuan JY Lim Julia Sze Lynn JSL Sanda Takaomi T Ooi Melissa M De Mel Sanjay S Soekojo Cinnie C Chen Yongxia Y Zhang Enfan E Cai Zhen Z Shen Peng P Ruan Jian J Chng Wee-Joo WJ

Blood cancer journal 20210212 2

Multiple myeloma (MM) is an aggressive plasma cell neoplasm characterized by genomic heterogeneity. Superenhancers (SEs) are defined as large clusters of enhancers in close genomic proximity, which regulate genes for maintaining cellular identity and promote oncogenic transcription to which cancer cells highly addicted. Here, we analyzed cis-regulatory elements in MM samples with H3K27ac ChIP-seq, to identify novel SE-associated genes involved in the myeloma pathogenesis. SEs and their associate ...[more]

PMID: 33579893

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Dataset Information

Myeloma-specific superenhancers affect genes of biological and clinical relevance in myeloma.

Publications

Myeloma-specific superenhancers affect genes of biological and clinical relevance in myeloma.

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