Scholarlink

<p>The <i>IKZF1</i> gene encodes IKAROS – a DNA binding protein that acts as a tumor suppressor in T-cell acute lymphoblastic leukemia (T-ALL). IKAROS can act as a transcriptional repressor via recruitment of histone deacetylase 1 (HDAC1) and chromatin remodeling, however the mechanisms through which IKAROS exerts its tumor suppressor function via heterochromatin in T-ALL are largely unknown. We studied human and mouse T-ALL using a loss-of-function and <i>IKZF</i>1 re-expression approach, along with primary human T-ALL, and normal human and mouse thymocytes to establish the role of IKAROS and HDAC1 in global regulation of facultative heterochromatin and transcriptional repression in T-ALL. Results identified novel IKAROS and HDAC1 functions in T-ALL: Both IKAROS and HDAC1 are essential for EZH2 histone methyltransferase activity and formation of facultative heterochromatin; recruitment of HDAC1 by IKAROS is critical for establishment of H3K27me3 histone modification and repression of active enhancers; and IKAROS-HDAC1 complexes promote formation and expansion of H3K27me3 Large Organized Chromatin lysine (K) domains (LOCKs) and Broad Genic Repression Domains (BGRDs) in T-ALL. Our results establish the central role of IKAROS and HDAC1 in activation of EZH2, global regulation of the facultative heterochromatin landscape, and silencing of active enhancers that regulate oncogene expression.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Critical roles of IKAROS and HDAC1 in regulation of heterochromatin and tumor suppression in T-cell acute lymphoblastic leukemia

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年6月24日

查看全文
  • Yali Ding,
  • Bing He,
  • Daniel Bogush,
  • Joseph Schramm,
  • Chingakham Singh,
  • Katarina Dovat,
  • Julia Randazzo,
  • Diwakar Tukaramrao,
  • Jeremy Hengst,
  • Charyguly Annageldiyev,
  • Avinash Kudva,
  • Dhimant Desai,
  • Arati Sharma,
  • Vladimir S. Spiegelman,
  • Suming Huang,
  • Chi T. Viet,
  • Glenn Dorsam,
  • Giselle Saulnier Scholler,
  • James Broach,
  • Feng Yue,
  • Sinisa Dovat

摘要

The IKZF1 gene encodes IKAROS – a DNA binding protein that acts as a tumor suppressor in T-cell acute lymphoblastic leukemia (T-ALL). IKAROS can act as a transcriptional repressor via recruitment of histone deacetylase 1 (HDAC1) and chromatin remodeling, however the mechanisms through which IKAROS exerts its tumor suppressor function via heterochromatin in T-ALL are largely unknown. We studied human and mouse T-ALL using a loss-of-function and IKZF1 re-expression approach, along with primary human T-ALL, and normal human and mouse thymocytes to establish the role of IKAROS and HDAC1 in global regulation of facultative heterochromatin and transcriptional repression in T-ALL. Results identified novel IKAROS and HDAC1 functions in T-ALL: Both IKAROS and HDAC1 are essential for EZH2 histone methyltransferase activity and formation of facultative heterochromatin; recruitment of HDAC1 by IKAROS is critical for establishment of H3K27me3 histone modification and repression of active enhancers; and IKAROS-HDAC1 complexes promote formation and expansion of H3K27me3 Large Organized Chromatin lysine (K) domains (LOCKs) and Broad Genic Repression Domains (BGRDs) in T-ALL. Our results establish the central role of IKAROS and HDAC1 in activation of EZH2, global regulation of the facultative heterochromatin landscape, and silencing of active enhancers that regulate oncogene expression.