GRHL2 motif is associated with intratumor heterogeneity of cis-regulatory elements in luminal breast cancer.
GRHL2 motif is associated with intratumor heterogeneity of cis-regulatory elements in luminal breast cancer.
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DOI：
10.1038/s41523-022-00438-6
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发表时间：
2022-06-08
影响因子：
5.9
通讯作者：
Maruyama, Reo
中科院分区：
文献类型：
--
作者：
Kumegawa, Kohei;Takahashi, Yoko;Saeki, Sumito;Yang, Liying;Nakadai, Tomoyoshi;Osako, Tomo;Mori, Seiichi;Noda, Tetsuo;Ohno, Shinji;Ueno, Takayuki;Maruyama, Reo
在乳腺癌患者中，肿瘤异质性与预后和治疗反应相关；然而，原发性肿瘤中存在的表观遗传多样性仍然未知。利用转座酶可及染色质单细胞测序（scATAC-seq），我们获得了来自16例乳腺癌患者的12452个细胞的染色质可及性谱，包括11个luminal亚型、1个luminal-HER2亚型、1个HER2+亚型和3个三阴性亚型。通过这一分析过程，肿瘤被分为癌细胞和肿瘤微环境，突出了包括雌激素受体（ER）信号在内的疾病相关途径的异质性。此外，在单个ER+肿瘤中发现了具有不同ER结合基序富集度的癌细胞簇共存。在ER基序富集程度较低的簇中，我们发现转录因子GRHL2是富集程度最高的基序，它与FOXA1协同启动内分泌抵抗。可达性分析显示，GRHL2结合元件可能调控接受激素治疗的患者中与内分泌抵抗、转移和不良预后相关的基因。总之，我们的研究表明，表观遗传异质性可能导致乳腺癌患者内分泌抵抗和预后不良，为进一步的癌症研究提供了大规模的资源。
In breast cancer patients, tumor heterogeneity is associated with prognosis and therapeutic response; however, the epigenetic diversity that exists in primary tumors remains unknown. Using a single-cell sequencing assay for transposase-accessible chromatin (scATAC-seq), we obtained the chromatin accessibility profiles of 12,452 cells from 16 breast cancer patients including 11 luminal, 1 luminal-HER2, 1 HER2+, and 3 triple-negative subtypes. Via this profiling process, tumors were classified into cancer cells and the tumor microenvironment, highlighting the heterogeneity of disease-related pathways including estrogen receptor (ER) signaling. Furthermore, the coexistence of cancer cell clusters with different ER binding motif enrichments was identified in a single ER+ tumor. In a cluster with reduced ER motif enrichment, we identified GRHL2, a transcription factor, as the most enriched motif, and it cooperated with FOXA1 to initiate endocrine resistance. Coaccessibility analysis revealed that GRHL2 binding elements potentially regulate genes associated with endocrine resistance, metastasis, and poor prognosis in patients that received hormonal therapy. Overall, our study suggests that epigenetic heterogeneity could lead to endocrine resistance and poor prognosis in breast cancer patients and it offers a large-scale resource for further cancer research.
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影响因子：
14.9
作者：
Colaprico A;Silva TC;Olsen C;Garofano L;Cava C;Garolini D;Sabedot TS;Malta TM;Pagnotta SM;Castiglioni I;Ceccarelli M;Bontempi G;Noushmehr H
通讯作者：
Noushmehr H
DOI：
10.15252/embj.2020107333
发表时间：
2021-06-01
期刊：
The EMBO journal
影响因子：
--
作者：
Pal B;Chen Y;Vaillant F;Capaldo BD;Joyce R;Song X;Bryant VL;Penington JS;Di Stefano L;Tubau Ribera N;Wilcox S;Mann GB;kConFab;Papenfuss AT;Lindeman GJ;Smyth GK;Visvader JE
通讯作者：
Visvader JE
影响因子：
3.3
作者：
Park, K;Kwak, K;Han, S
通讯作者：
Han, S
影响因子：
8.8
作者：
Cocce, Kimberly J.;Jasper, Jeff S.;McDonnell, Donald P.
通讯作者：
McDonnell, Donald P.
影响因子：
64.8
作者：
Curtis, Christina;Shah, Sohrab P.;Chin, Suet-Feung;Turashvili, Gulisa;Rueda, Oscar M.;Dunning, Mark J.;Speed, Doug;Lynch, Andy G.;Samarajiwa, Shamith;Yuan, Yinyin;Graef, Stefan;Ha, Gavin;Haffari, Gholamreza;Bashashati, Ali;Russell, Roslin;McKinney, Steven;Langerod, Anita;Green, Andrew;Provenzano, Elena;Wishart, Gordon;Pinder, Sarah;Watson, Peter;Markowetz, Florian;Murphy, Leigh;Ellis, Ian;Purushotham, Arnie;Borresen-Dale, Anne-Lise;Brenton, James D.;Tavare, Simon;Caldas, Carlos;Aparicio, Samuel
通讯作者：
Aparicio, Samuel