Genome-wide profiling of transcription factor activity in primary liver cancer using single-cell ATAC sequencing

Amanda J Craig; Maruhen A Datsch Silveira; Lichun Ma; Mahler Revsine; Limin Wang; Sophia Heinrich; Zachary Rae; Allison Ruchinskas; Kimia Dadkhah; Whitney Do; Shay Behrens; Farid R Mehrabadi; Dana A Dominguez; Marshonna Forgues; Anuradha Budhu; Jittiporn Chaisaingmongkol; Jonathan M Hernandez; Jeremy L Davis; Bao Tran; Jens U Marquardt; Mathuros Ruchirawat; Michael Kelly; Tim F Greten; Xin W Wang

doi:10.1016/j.celrep.2023.113446

Genome-wide profiling of transcription factor activity in primary liver cancer using single-cell ATAC sequencing

Cell Rep. 2023 Nov 28;42(11):113446. doi: 10.1016/j.celrep.2023.113446. Epub 2023 Nov 18.

Authors

Amanda J Craig¹, Maruhen A Datsch Silveira¹, Lichun Ma², Mahler Revsine¹, Limin Wang¹, Sophia Heinrich³, Zachary Rae⁴, Allison Ruchinskas⁴, Kimia Dadkhah⁴, Whitney Do¹, Shay Behrens⁵, Farid R Mehrabadi¹, Dana A Dominguez⁶, Marshonna Forgues¹, Anuradha Budhu⁷, Jittiporn Chaisaingmongkol⁸, Jonathan M Hernandez⁹, Jeremy L Davis¹⁰, Bao Tran⁴, Jens U Marquardt¹¹, Mathuros Ruchirawat⁸, Michael Kelly⁴, Tim F Greten¹², Xin W Wang¹³

Affiliations

¹ Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
² Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA; Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA; Liver Cancer Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
³ Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA; Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hanover Medical School, 30159 Hanover, Germany.
⁴ Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 20701, USA.
⁵ Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA; Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
⁶ Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA; Department of Surgical Oncology, City of Hope National Medical Center, Duarte, CA 91010, USA.
⁷ Liver Cancer Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
⁸ Laboratory of Chemical Carcinogenesis, Chulabhorn Research Institute, Bangkok 10210, Thailand; Center of Excellence on Environmental Health and Toxicology, Office of Higher Education Commission, Ministry of Higher Education, Science, Research and Innovation, Bangkok 10400, Thailand.
⁹ Liver Cancer Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA; Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
¹⁰ Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
¹¹ Department of Medicine I, University of Lübeck, 23552 Lübeck, Germany.
¹² Liver Cancer Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA; Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
¹³ Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA; Liver Cancer Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. Electronic address: xw3u@nih.gov.

Abstract

Primary liver cancer (PLC) consists of two main histological subtypes; hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). The role of transcription factors (TFs) in malignant hepatobiliary lineage commitment between HCC and iCCA remains underexplored. Here, we present genome-wide profiling of transcription regulatory elements of 16 PLC patients using single-cell assay for transposase accessible chromatin sequencing. Single-cell open chromatin profiles reflect the compositional diversity of liver cancer, identifying both malignant and microenvironment component cells. TF motif enrichment levels of 31 TFs strongly discriminate HCC from iCCA tumors. These TFs are members of the nuclear/retinoid receptor, POU, or ETS motif families. POU factors are associated with prognostic features in iCCA. Overall, nuclear receptors, ETS and POU TF motif families delineate transcription regulation between HCC and iCCA tumors, which may be relevant to development and selection of PLC subtype-specific therapeutics.

Keywords: CP: Cancer; ETS; POU; hepatocellular carcinoma; intrahepatic cholangiocarcinoma; nuclear receptors; primary liver cancer; retinoid receptors; scATAC-seq; transcription factor.

Published by Elsevier Inc.

Publication types

Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural

MeSH terms

Bile Duct Neoplasms* / pathology
Bile Ducts, Intrahepatic / pathology
Carcinoma, Hepatocellular* / genetics
Carcinoma, Hepatocellular* / pathology
Cholangiocarcinoma* / genetics
Cholangiocarcinoma* / pathology
Chromatin
Humans
Liver Neoplasms* / genetics
Liver Neoplasms* / pathology
Transcription Factors / genetics
Tumor Microenvironment

Substances

Transcription Factors
Chromatin

Abstract

Publication types

MeSH terms

Substances

Grants and funding