1003 – ESTABLISHING SAMD1-DEPENDENT ACTIVITIES IN HEMATOPOIESIS AND ERYTHROPOIESIS

IF 2.5 4区 医学 Q2 HEMATOLOGY
Kyle Hewitt
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引用次数: 0

Abstract

Transitions between cell progenitors and progeny depend on precise transcriptional mechanisms to adjust gene expression programs. The sterile alpha motif-containing 1 (SAMD1) gene encodes a transcription factor which coordinates histone modifications during embryonic stem cell exit from pluripotency. SAMD1 is expressed throughout many biological systems, but its role in hematopoiesis is unknown. SAMD1 prefers to bind chromatin at unmethylated CpG islands (CGIs), where it acts primarily as a transcriptional repressor. SAMD1 interacts with and promotes the function of lysine demethylase LSD1, which blocks terminal erythropoiesis. Samd1 knockout is embryonic lethal in mice. To test Samd1 in hematopoiesis, we performed competitive transplant experiments in mice using shRNA knockdown HSCs. Samd1 knockdown versus control HSCs revealed an increase in HSC repopulation with 3.9-fold more CD45.2+ after 8 weeks. We conducted scRNA-seq and chromatin occupancy profiling in Samd1 knockdown and knockout cells, revealing that Samd1 regulated a genetic network consistent with a role in stem cell self-renewal, including the repression of erythroid-specific genes. Ongoing experiments are testing whether SAMD1 functions in partnership with the lysine demethylase LSD1 during erythropoiesis. Both SAMD1 and LSD1 are commonly upregulated in acute myeloid leukemia (AML), and high expression is correlated with poor prognosis. These mechanisms may be exploitable to improve HSC expansion ex vivo. Linking Samd1 function to signaling, transcription, or other cellular functions opens the door to translational avenues for studying the contribution of Samd1 in hematologic pathologies.

1003 - 确定 Samd1 在造血和红细胞生成中的依赖性活动
细胞祖细胞和后代之间的转变取决于调整基因表达程序的精确转录机制。含不育α基序的1(SAMD1)基因编码一种转录因子,在胚胎干细胞从多能性中退出的过程中协调组蛋白修饰。SAMD1在许多生物系统中都有表达,但其在造血中的作用尚不清楚。SAMD1 喜欢与未甲基化的 CpG 岛(CGIs)上的染色质结合,在那里主要起转录抑制作用。SAMD1 与赖氨酸去甲基化酶 LSD1 相互作用并促进其功能,而 LSD1 会阻碍末端红细胞生成。Samd1 基因敲除会导致小鼠胚胎死亡。为了测试 Samd1 在造血过程中的作用,我们使用 shRNA 敲除造血干细胞在小鼠体内进行了竞争性移植实验。Samd1 基因敲除与对照造血干细胞相比,8 周后造血干细胞再填充增加,CD45.2+增加了 3.9 倍。我们在Samd1敲除和敲除细胞中进行了scRNA-seq和染色质占位谱分析,发现Samd1调控的基因网络与干细胞自我更新中的作用一致,包括抑制红细胞特异性基因。正在进行的实验正在测试SAMD1是否在红细胞生成过程中与赖氨酸去甲基化酶LSD1共同发挥作用。在急性髓性白血病(AML)中,SAMD1 和 LSD1 通常都会上调,而且高表达与预后不良有关。这些机制可用于改善体内造血干细胞的扩增。将 Samd1 的功能与信号传导、转录或其他细胞功能联系起来,为研究 Samd1 在血液病中的作用打开了一扇通往转化途径的大门。
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来源期刊
Experimental hematology
Experimental hematology 医学-血液学
CiteScore
5.30
自引率
0.00%
发文量
84
审稿时长
58 days
期刊介绍: Experimental Hematology publishes new findings, methodologies, reviews and perspectives in all areas of hematology and immune cell formation on a monthly basis that may include Special Issues on particular topics of current interest. The overall goal is to report new insights into how normal blood cells are produced, how their production is normally regulated, mechanisms that contribute to hematological diseases and new approaches to their treatment. Specific topics may include relevant developmental and aging processes, stem cell biology, analyses of intrinsic and extrinsic regulatory mechanisms, in vitro behavior of primary cells, clonal tracking, molecular and omics analyses, metabolism, epigenetics, bioengineering approaches, studies in model organisms, novel clinical observations, transplantation biology and new therapeutic avenues.
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