PO.MCB06.04 · 分子与细胞生物学

Arid1a 指导乳腺上皮细胞的谱系定向

Arid1a directs lineage specification in mammary epithelial cells

编号 3219 展板 1 时间 4/20 02:00–05:00 区域 Section 21 主讲 Erik Ladewig, PhD

分会场 Epigenomics

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作者与单位 Authors & Affiliations

Erik Ladewig¹, Amaia Arruabarrena-Aristorena², Estelle Deby³, Srushti Kittane⁴, Fresia Pareja⁵, Ryan Blawski⁶, Yangzhenyu Gao⁷, Laura Baldino¹, Vito Rebecca⁴, Emiliano Cocco⁸, Hongkai Ji⁴, Pau Castel⁹, Christina Leslie¹, Wouter Karthaus¹⁰, Eneda Toska¹¹

¹Memorial Sloan Kettering Cancer Center, New York, NY,²Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country UPV/EHU, Bilbao, Spain,³School of Life Sciences, Swiss Institute for Experimental Cancer Research (ISREC), Lausanne, Switzerland,⁴Johns Hopkins University, Baltimore, MD,⁵Memorial Sloan Kettering Cancer Center, New York, NY,⁶Johns Hopkins Medicine, Baltimore, MD,⁷Biochemistry and Molecular Biology, Johns Hopkins University, Baltimore, MD,⁸University of Miami, Miami, FL,⁹NYU Grossman School of Medicine, San Francisco, CA,¹⁰The Ecole polytechnique fédérale de Lausanne, Lausanne, Switzerland,¹¹Johns Hopkins University School of Medicine, Baltimore, MD

摘要 Abstract

中文摘要

表观遗传调控对乳腺发育至关重要，然而控制乳腺上皮细胞命运的特定染色质重塑因子仍未被充分明确。SWI/SNF 染色质重塑复合体亚基的突变发生在超过 20% 的人类癌症中，其中 ARID1A 是最常发生改变的。在乳腺癌中，ARID1A 功能缺失突变在转移性雌激素受体阳性（ER⁺）疾病中富集，并与内分泌治疗耐药相关。为在体内界定 Arid1a 的发育作用，我们构建了乳腺上皮特异性 Arid1a 缺失的小鼠。这些动物表现出导管分支紊乱和终末端芽形成异常。源自 Arid1a 缺陷组织的乳腺类器官进一步揭示了异常的囊性形态和分化受损。为剖析 Arid1a 缺失的分子后果，我们进行了单细胞多组学分析，结合同一细胞的单核 RNA 和染色质可及性测序，以及 H3K27ac 和 BRG1 CUT&RUN-seq。Arid1a 缺失导致正常乳腺上皮谱系结构的崩溃，单细胞分析显示无法维持基底、腔上皮祖细胞和腺泡身份。相反，Arid1a 缺陷细胞被限制在一种未分化的腔激素样状态，其特征是雌激素受体信号传导能力降低。染色质分析揭示了深刻的重塑，包括在谱系决定性转录因子（TF）如 Foxa1、Gata3 和 Sox9 处可及性降低和 SWI/SNF 靶向受损。CRISPR/Cas9 混合功能缺失筛选鉴定出 Foxa1 和 Meis1 为必需的调控因子，其缺失重现了 Arid1a 敲除表型，将它们定位为乳腺细胞命运定向所需的下游效应因子。值得注意的是，Meis1 成为一种以往未被识别的腔激素身份调控因子。我们的工作为理解 Arid1a 如何重塑正常乳腺发育中的染色质格局和转录网络提供了框架。通过鉴定谱系特异性 TF 基序和关键调控因子（如 Meis1），我们识别出靶向治疗干预的新机会。

查看英文原文 English abstract

Epigenetic regulation is essential for mammary gland development, yet the specific chromatin remodelers that govern mammary epithelial cell fate remain poorly defined. Mutations in SWI/SNF chromatin remodeling complex subunits occur in more than 20% of human cancers, with ARID1A being the most frequently altered. In breast cancer, ARID1A loss of function mutations are enriched in metastatic estrogen receptor-positive (ER⁺) disease and associated with endocrine therapy resistance. To define the developmental role of Arid1a in vivo, we generated mice with mammary epithelium specific Arid1a deletion. These animals displayed disrupted ductal branching and aberrant terminal end bud formation. Mammary organoids derived from Arid1a deficient tissue further revealed abnormal cystic morphology and impaired differentiation. To dissect the molecular consequences of Arid1a loss, we performed single cell multiomic profiling that combine single nucleus RNA and chromatin accessibility sequencing from the same cells, together with H3K27ac and BRG1 CUT&RUN-seq. Arid1a loss caused a collapse of normal mammary epithelial lineage architecture, with single cell analyses showing failure to maintain basal, luminal progenitor, and alveolar identities. Instead, Arid1a deficient cells were restricted to an undifferentiated luminal hormonal like state characterized by reduced estrogen receptor signaling competence. Chromatin profiling revealed profound remodeling, including decreased accessibility and impaired SWI/SNF targeting at lineage defining transcription factors (TF) such as Foxa1, Gata3, and Sox9. A CRISPR/Cas9 pooled loss of function screen identified Foxa1 and Meis1 as essential regulators whose deletion recapitulated the Arid1a null phenotype, positioning them as downstream effectors required for mammary cell fate specification. Notably, Meis1 emerged as a previously unrecognized regulator of luminal hormonal identity. Our work provides a framework for understanding how Arid1a rewires the chromatin landscape and transcriptional network in normal mammary development. By identifying lineage specific TF motifs and critical regulators like Meis1, we identify new opportunities for targeted therapeutic intervention.

利益披露 Disclosure

E. Ladewig, None.. A. Arruabarrena-Aristorena, None.. E. Deby, None.. S. Kittane, None.. Y. Gao, None.

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