Single-Cell Transcriptional and Epigenetic Profiles of Male Breast Cancer Nominate Salient Cancer-Specific Enhancers.
Single-Cell Transcriptional and Epigenetic Profiles of Male Breast Cancer Nominate Salient Cancer-Specific Enhancers.
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男性乳腺癌的单细胞转录和表观遗传学特征提名了明显的癌症特异性增强子。
DOI：
10.3390/ijms241713053
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发表时间：
2023-08-22
影响因子：
5.6
通讯作者：
Franco, Hector L.
中科院分区：
文献类型：
--
作者：
Kim, Hyunsoo;Wisniewska, Kamila;Regner, Matthew J.;Thennavan, Aatish;Spanheimer, Philip M.;Franco, Hector L.
关键词：
男性乳腺癌约占所有乳腺癌诊断的1%，尽管男性和女性乳腺癌之间有一些相似之处，但关于男性乳腺癌的现有数据很少，因此很难建立有针对性的治疗方法。到目前为止，大多数男性乳腺癌(MBC)是根据为女性乳腺癌(FBC)制定的方案进行治疗的。因此，用更高的分辨率定义MBC的转录和表观遗传图景对于开发更好的治疗干预途径至关重要。在这项研究中，我们提出了匹配转录(scRNA-seq)和表观遗传(scATAC-seq)图谱，在单细胞分辨率下，两种治疗方法在手术切除后立即处理的原始MBC肿瘤。这些数据能够检测免疫、间质和恶性细胞类型的男性和女性乳腺肿瘤之间的差异表达基因，以突出几个可能具有治疗意义的基因。值得注意的是，与女性相比，MYC靶基因和mTORC1信号基因在MBC的恶性细胞中显著上调。为了了解MBC的调控格局如何产生这些男性特有的基因表达模式，我们利用scATAC-seq数据系统地将染色质可及性的变化与每种细胞类型内基因表达的变化联系起来。我们观察到了几个显著增强子的癌症特异性重连，并假设这些增强子比谱系特异性增强子有更高的调节负荷。我们突出了两个以前未加注释的ANXA2和PRDX4基因表达的癌细胞特异性增强子的例子，并展示了LAMB3和CD47在男性乳腺癌细胞中的超级增强子调控的证据。总体而言，这个数据集注释了男性乳腺肿瘤的临床相关调控网络，提供了一个有用的资源，扩大了我们目前对MBC生物学基础上的基因表达程序的理解。
Male breast cancer represents about 1% of all breast cancer diagnoses and, although there are some similarities between male and female breast cancer, the paucity of data available on male breast cancer makes it difficult to establish targeted therapies. To date, most male breast cancers (MBCs) are treated according to protocols established for female breast cancer (FBC). Thus, defining the transcriptional and epigenetic landscape of MBC with improved resolution is critical for developing better avenues for therapeutic intervention. In this study, we present matched transcriptional (scRNA-seq) and epigenetic (scATAC-seq) profiles at single-cell resolution of two treatment naïve MBC tumors processed immediately after surgical resection. These data enable the detection of differentially expressed genes between male and female breast tumors across immune, stromal, and malignant cell types, to highlight several genes that may have therapeutic implications. Notably, MYC target genes and mTORC1 signaling genes were significantly upregulated in the malignant cells of MBC compared to the female counterparts. To understand how the regulatory landscape of MBC gives rise to these male-specific gene expression patterns, we leveraged the scATAC-seq data to systematically link changes in chromatin accessibility to changes in gene expression within each cell type. We observed cancer-specific rewiring of several salient enhancers and posit that these enhancers have a higher regulatory load than lineage-specific enhancers. We highlight two examples of previously unannotated cancer-cell-specific enhancers of ANXA2 and PRDX4 gene expression and show evidence for super-enhancer regulation of LAMB3 and CD47 in male breast cancer cells. Overall, this dataset annotates clinically relevant regulatory networks in male breast tumors, providing a useful resource that expands our current understanding of the gene expression programs that underlie the biology of MBC.
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影响因子：
8
作者：
Cassandri, Matteo;Butera, Alessio;Melino, Gerry
通讯作者：
Melino, Gerry
影响因子：
14.9
作者：
Bailey TL;Johnson J;Grant CE;Noble WS
通讯作者：
Noble WS
单细胞染色质可及性揭示了调节变化的原理。
影响因子：
64.8
作者：
Buenrostro JD;Wu B;Litzenburger UM;Ruff D;Gonzales ML;Snyder MP;Chang HY;Greenleaf WJ
通讯作者：
Greenleaf WJ
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
3.8
作者：
Gibbs, Lee D.;Chaudhary, Pankaj;Vishwanatha, Jamboor K.
通讯作者：
Vishwanatha, Jamboor K.