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A systematic dissection of the epigenomic heterogeneity of lung adenocarcinoma reveals two different subclasses with distinct prognosis and core regulatory networks

BACKGROUND: Lung adenocarcinoma (LUAD) is a highly malignant and heterogeneous tumor that involves various oncogenic genetic alterations. Epigenetic processes play important roles in lung cancer development. However, the variation in enhancer and super-enhancer landscapes of LUAD patients remains la...

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Autores principales: Yuan, Chongze, Chen, Haojie, Tu, Shiqi, Huang, Hsin-Yi, Pan, Yunjian, Gui, Xiuqi, Kuang, Muyu, Shen, Xuxia, Zheng, Qiang, Zhang, Yang, Cheng, Chao, Hong, Hui, Tao, Xiaoting, Peng, Yizhou, Yao, Xingxin, Meng, Feilong, Ji, Hongbin, Shao, Zhen, Sun, Yihua
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127276/
https://www.ncbi.nlm.nih.gov/pubmed/34001209
http://dx.doi.org/10.1186/s13059-021-02376-1
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author Yuan, Chongze
Chen, Haojie
Tu, Shiqi
Huang, Hsin-Yi
Pan, Yunjian
Gui, Xiuqi
Kuang, Muyu
Shen, Xuxia
Zheng, Qiang
Zhang, Yang
Cheng, Chao
Hong, Hui
Tao, Xiaoting
Peng, Yizhou
Yao, Xingxin
Meng, Feilong
Ji, Hongbin
Shao, Zhen
Sun, Yihua
author_facet Yuan, Chongze
Chen, Haojie
Tu, Shiqi
Huang, Hsin-Yi
Pan, Yunjian
Gui, Xiuqi
Kuang, Muyu
Shen, Xuxia
Zheng, Qiang
Zhang, Yang
Cheng, Chao
Hong, Hui
Tao, Xiaoting
Peng, Yizhou
Yao, Xingxin
Meng, Feilong
Ji, Hongbin
Shao, Zhen
Sun, Yihua
author_sort Yuan, Chongze
collection PubMed
description BACKGROUND: Lung adenocarcinoma (LUAD) is a highly malignant and heterogeneous tumor that involves various oncogenic genetic alterations. Epigenetic processes play important roles in lung cancer development. However, the variation in enhancer and super-enhancer landscapes of LUAD patients remains largely unknown. To provide an in-depth understanding of the epigenomic heterogeneity of LUAD, we investigate the H3K27ac histone modification profiles of tumors and adjacent normal lung tissues from 42 LUAD patients and explore the role of epigenetic alterations in LUAD progression. RESULTS: A high intertumoral epigenetic heterogeneity is observed across the LUAD H3K27ac profiles. We quantitatively model the intertumoral variability of H3K27ac levels at proximal gene promoters and distal enhancers and propose a new epigenetic classification of LUAD patients. Our classification defines two LUAD subgroups which are highly related to histological subtypes. Group II patients have significantly worse prognosis than group I, which is further confirmed in the public TCGA-LUAD cohort. Differential RNA-seq analysis between group I and group II groups reveals that those genes upregulated in group II group tend to promote cell proliferation and induce cell de-differentiation. We construct the gene co-expression networks and identify group-specific core regulators. Most of these core regulators are linked with group-specific regulatory elements, such as super-enhancers. We further show that CLU is regulated by 3 group I-specific core regulators and works as a novel tumor suppressor in LUAD. CONCLUSIONS: Our study systematically characterizes the epigenetic alterations during LUAD progression and provides a new classification model that is helpful for predicting patient prognosis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13059-021-02376-1.
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spelling pubmed-81272762021-05-18 A systematic dissection of the epigenomic heterogeneity of lung adenocarcinoma reveals two different subclasses with distinct prognosis and core regulatory networks Yuan, Chongze Chen, Haojie Tu, Shiqi Huang, Hsin-Yi Pan, Yunjian Gui, Xiuqi Kuang, Muyu Shen, Xuxia Zheng, Qiang Zhang, Yang Cheng, Chao Hong, Hui Tao, Xiaoting Peng, Yizhou Yao, Xingxin Meng, Feilong Ji, Hongbin Shao, Zhen Sun, Yihua Genome Biol Research BACKGROUND: Lung adenocarcinoma (LUAD) is a highly malignant and heterogeneous tumor that involves various oncogenic genetic alterations. Epigenetic processes play important roles in lung cancer development. However, the variation in enhancer and super-enhancer landscapes of LUAD patients remains largely unknown. To provide an in-depth understanding of the epigenomic heterogeneity of LUAD, we investigate the H3K27ac histone modification profiles of tumors and adjacent normal lung tissues from 42 LUAD patients and explore the role of epigenetic alterations in LUAD progression. RESULTS: A high intertumoral epigenetic heterogeneity is observed across the LUAD H3K27ac profiles. We quantitatively model the intertumoral variability of H3K27ac levels at proximal gene promoters and distal enhancers and propose a new epigenetic classification of LUAD patients. Our classification defines two LUAD subgroups which are highly related to histological subtypes. Group II patients have significantly worse prognosis than group I, which is further confirmed in the public TCGA-LUAD cohort. Differential RNA-seq analysis between group I and group II groups reveals that those genes upregulated in group II group tend to promote cell proliferation and induce cell de-differentiation. We construct the gene co-expression networks and identify group-specific core regulators. Most of these core regulators are linked with group-specific regulatory elements, such as super-enhancers. We further show that CLU is regulated by 3 group I-specific core regulators and works as a novel tumor suppressor in LUAD. CONCLUSIONS: Our study systematically characterizes the epigenetic alterations during LUAD progression and provides a new classification model that is helpful for predicting patient prognosis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13059-021-02376-1. BioMed Central 2021-05-17 /pmc/articles/PMC8127276/ /pubmed/34001209 http://dx.doi.org/10.1186/s13059-021-02376-1 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Yuan, Chongze
Chen, Haojie
Tu, Shiqi
Huang, Hsin-Yi
Pan, Yunjian
Gui, Xiuqi
Kuang, Muyu
Shen, Xuxia
Zheng, Qiang
Zhang, Yang
Cheng, Chao
Hong, Hui
Tao, Xiaoting
Peng, Yizhou
Yao, Xingxin
Meng, Feilong
Ji, Hongbin
Shao, Zhen
Sun, Yihua
A systematic dissection of the epigenomic heterogeneity of lung adenocarcinoma reveals two different subclasses with distinct prognosis and core regulatory networks
title A systematic dissection of the epigenomic heterogeneity of lung adenocarcinoma reveals two different subclasses with distinct prognosis and core regulatory networks
title_full A systematic dissection of the epigenomic heterogeneity of lung adenocarcinoma reveals two different subclasses with distinct prognosis and core regulatory networks
title_fullStr A systematic dissection of the epigenomic heterogeneity of lung adenocarcinoma reveals two different subclasses with distinct prognosis and core regulatory networks
title_full_unstemmed A systematic dissection of the epigenomic heterogeneity of lung adenocarcinoma reveals two different subclasses with distinct prognosis and core regulatory networks
title_short A systematic dissection of the epigenomic heterogeneity of lung adenocarcinoma reveals two different subclasses with distinct prognosis and core regulatory networks
title_sort systematic dissection of the epigenomic heterogeneity of lung adenocarcinoma reveals two different subclasses with distinct prognosis and core regulatory networks
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127276/
https://www.ncbi.nlm.nih.gov/pubmed/34001209
http://dx.doi.org/10.1186/s13059-021-02376-1
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