相关实验视频

Updated: Jun 4, 2025

Use of Hematopoietic Stem Cell Transplantation to Assess the Origin of Myelodysplastic Syndrome

Use of Hematopoietic Stem Cell Transplantation to Assess the Origin of Myelodysplastic Syndrome

Published on: October 3, 2018

一个突变的ASXL1-BAP1-EHMT复合体有助于在克隆性血液形成和慢性单核细胞白血病中导致异性染色素功能障碍

Zhen Dong^1,2,3,4, Hugo Sepulveda^1,2,3,4,5, Leo J Arteaga-Vazquez¹

¹Department of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037.

Proceedings of the National Academy of Sciences of the United States of America

|January 3, 2025

概括

在克隆性血液形成中常见的ASXL1突变,通过减少关键基因素标记来破坏异色素蛋白. 这导致可转移元素表达和炎症相关基因增加,影响健康.

科学领域:

表观遗传学和基因调控
血液形成和癌症生物学
疾病的分子机制.

背景情况:

与年龄相关的克隆性血液形成 (CH) 涉及ASXL1,DNMT3A和TET2等基因的突变,与髓状瘤和死亡率有关.
虽然已知DNMT3A和TET2在DNA甲基化中的作用,但将ASXL1突变与CH相关联的机制尚不清楚.
ASXL1突变导致截断的蛋白质,增强PR-DUB复合物的二维基因酶活性,影响H2AK119Ub水平.

研究的目的:

阐明突变ASXL1对克隆性血液形成有所贡献的分子机制.
为了研究ASXL1突变对异色素蛋白完整性和基因表达的影响.
探索ASXL1驱动的表观遗传变化与相关病理之间的联系.

主要方法:

对ASXL1突变蛋白与基因素甲基转移酶复合体 (EHMT1-EHMT2) 相互作用的分析.
在小鼠模型 (Asxl1tm/+小鼠) 和人类样本 (CMML患者) 中对基因组变异 (H3K9me2,H3K9me3,H2AK119Ub) 的全基因组评估.
可转移元素 (TE) 和卫星重复表达的量化,以及附近的基因表达,包括干扰素诱导基因 (ISG).

主要成果:

ASXL1突变蛋白与EHMT1-EHMT2相互作用,影响H3K9me1/me2的产生.
来自老老Axl1tm/+小鼠的髓状细胞显示H3K9me2,H3K9me3和H2AK119Ub.Ub.的全基因组降低.
在突变小鼠和CMML患者中观察到增加的TE和卫星重复表达,以及升高的ISG表达.

结论:

突变ASXL1通过降低H3K9me2/3和H2AK119Ub.Ub.的方式,以年龄依赖的方式损害异性染色体完整性 (构成性和可选性).
减少的异色色素标记导致可转移元素和卫星重复的表达增加.
这种异常基因表达,特别是ISGs的异常基因表达,可能会导致与CH和CMML相关的炎症和恶性表型.

关键词:

在CMMLML中,CMML是CMML.EHMT1/2 (GLP/G9a) 的使用情况克隆性血液形成 (clonal hematopoiesis) 是一种细胞形成的过程.异性染色是一种异性染色.聚合体反应-脱基酶 (PR-DUB) 复合体

更多相关视频

Proliferation and Differentiation of Murine Myeloid Precursor 32D/G-CSF-R Cells

Proliferation and Differentiation of Murine Myeloid Precursor 32D/G-CSF-R Cells

Published on: February 21, 2018

In Vitro Differentiation Model of Human Normal Memory B Cells to Long-lived Plasma Cells

In Vitro Differentiation Model of Human Normal Memory B Cells to Long-lived Plasma Cells

Published on: January 20, 2019

相关概念视频

Lineage Commitment

Lineage Commitment

Commitment is the process whereby stem cells:

Pleiotropy

Pleiotropy

Pleiotropy is the phenomenon in which a single gene impacts multiple, seemingly unrelated phenotypic traits. For example, defects in the SOX10 gene cause Waardenburg Syndrome Type 4, or WS4, which can cause defects in pigmentation, hearing impairments, and an absence of intestinal contractions necessary for elimination. This diversity of phenotypes results from the expression pattern of SOX10 in early embryonic and fetal development. SOX10 is found in neural crest cells that form melanocytes,...

Inheritance of Chromatin Structures

Inheritance of Chromatin Structures

Epigenetics is the study of inherited changes in a cell's phenotype without changing the DNA sequences. It provides a form of memory for the differential gene expression pattern to maintain cell lineage, position-effect variegation, dosage compensation, and maintenance of chromatin structures such as telomeres and centromeres. For example, the structure and location of the centromere on chromosomes are epigenetically inherited. Its functionality is not dictated or ensured by the underlying...

Heterochromatin

Heterochromatin

The extent of chromatin compaction can be studied by staining chromatin using specific DNA binding dyes. Under the microscope, the dense-compacted regions that take up more dye are called heterochromatin. Heterochromatin is further classified into two forms – constitutive heterochromatin and facultative heterochromatin.
Constitutive heterochromatin: It is a highly compact region of chromatin that is mostly concentrated in the centromere and telomere. Unlike euchromatin, the amino acid at...