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

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. MarquardtMathuros Ruchirawat, Michael Kelly, Tim F. Greten, Xin W. Wang^*

^*Corresponding author for this work

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.

Original language	English
Article number	113446
Journal	Cell Reports
Volume	42
Issue number	11
Pages (from-to)	113446
ISSN	2211-1247
DOIs	https://doi.org/10.1016/j.celrep.2023.113446
Publication status	Published - 28.11.2023

Funding

Support from CCR Single Cell Analysis Facility for single-cell RNA-Seq captures, library preparation, sequencing and primary data processing was funded by FNLCR Contract 75N91019D00024. This work utilized the computational resources of the NIH HPC Biowulf cluster (http://hpc.nih.gov). This work was supported by grants (Z01 BC 010877, Z01 BC 010876, Z01 BC 010313, and ZIA BC 011870) from the intramural research program of the Center for Cancer Research, National Cancer Institute of the United States. J.U.M. was supported by a grant from the Wilhelm Sander Foundation (2021.089.1). BioRender software was used to generate the graphical abstract. Conceptualization, A.J.C. and X.W.W.; software, A.J.C. L.M. M.R. K.D. and F.R.M.; validation, A.J.C.; formal analysis, A.J.C. L.M. M.R. L.W. Z.R. A.R. K.D. W.D. S.B. F.R.M. M.A.D.S. M.F. B.T. and M.K.; resources, J.C. J.M.H. J.L.D. J.U.M. M.R. and T.F.G.; data curation, A.J.C. L.M. M.R. W.D. S.B. and D.A.D.; writing – original draft, A.J.C.; writing – review & editing, A.J.C. M.A.D.S. and X.W.W.; visualization, A.J.C. L.M. M.A.D.S. and W.D.; supervision, X.W.W.; project administration, A.J.C.; funding acquisition, X.W.W. The authors declare no competing interests. Support from CCR Single Cell Analysis Facility for single-cell RNA-Seq captures, library preparation, sequencing and primary data processing was funded by FNLCR Contract 75N91019D00024 . This work utilized the computational resources of the NIH HPC Biowulf cluster ( http://hpc.nih.gov ). This work was supported by grants ( Z01 BC 010877 , Z01 BC 010876 , Z01 BC 010313 , and ZIA BC 011870 ) from the intramural research program of the Center for Cancer Research , National Cancer Institute of the United States. J.U.M. was supported by a grant from the Wilhelm Sander Foundation ( 2021.089.1 ). BioRender software was used to generate the graphical abstract.

Research Areas and Centers

Research Area: Luebeck Integrated Oncology Network (LION)
Centers: University Cancer Center Schleswig-Holstein (UCCSH)

DFG Research Classification Scheme

2.22-14 Hematology, Oncology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2023.113446

Cite this

Craig, A. J., Silveira, M. A. D., Ma, L., Revsine, M., Wang, L., Heinrich, S., Rae, Z., Ruchinskas, A., Dadkhah, K., Do, W., Behrens, S., Mehrabadi, F. R., Dominguez, D. A., Forgues, M., Budhu, A., Chaisaingmongkol, J., Hernandez, J. M., Davis, J. L., Tran, B., ... Wang, X. W. (2023). Genome-wide profiling of transcription factor activity in primary liver cancer using single-cell ATAC sequencing. Cell Reports, 42(11), 113446. Article 113446. https://doi.org/10.1016/j.celrep.2023.113446

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

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.",

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

note = "Publisher Copyright: {\textcopyright} 2023",

year = "2023",

month = nov,

day = "28",

doi = "10.1016/j.celrep.2023.113446",

language = "English",

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Craig, AJ, Silveira, MAD, Ma, L, Revsine, M, Wang, L, Heinrich, S, Rae, Z, Ruchinskas, A, Dadkhah, K, Do, W, Behrens, S, Mehrabadi, FR, Dominguez, DA, Forgues, M, Budhu, A, Chaisaingmongkol, J, Hernandez, JM, Davis, JL, Tran, B, Marquardt, JU, Ruchirawat, M, Kelly, M, Greten, TF & Wang, XW 2023, 'Genome-wide profiling of transcription factor activity in primary liver cancer using single-cell ATAC sequencing', Cell Reports, vol. 42, no. 11, 113446, pp. 113446. https://doi.org/10.1016/j.celrep.2023.113446

TY - JOUR

T1 - Genome-wide profiling of transcription factor activity in primary liver cancer using single-cell ATAC sequencing

AU - Craig, Amanda J.

AU - Silveira, Maruhen A.Datsch

AU - Ma, Lichun

AU - Revsine, Mahler

AU - Wang, Limin

AU - Heinrich, Sophia

AU - Rae, Zachary

AU - Ruchinskas, Allison

AU - Dadkhah, Kimia

AU - Do, Whitney

AU - Behrens, Shay

AU - Mehrabadi, Farid R.

AU - Dominguez, Dana A.

AU - Forgues, Marshonna

AU - Budhu, Anuradha

AU - Chaisaingmongkol, Jittiporn

AU - Hernandez, Jonathan M.

AU - Davis, Jeremy L.

AU - Tran, Bao

AU - Marquardt, Jens U.

AU - Ruchirawat, Mathuros

AU - Kelly, Michael

AU - Greten, Tim F.

AU - Wang, Xin W.

PY - 2023/11/28

Y1 - 2023/11/28

N2 - 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.

AB - 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.

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UR - https://www.mendeley.com/catalogue/f458574b-e2cc-315c-a088-ae5528a64649/

U2 - 10.1016/j.celrep.2023.113446

DO - 10.1016/j.celrep.2023.113446

M3 - Journal articles

C2 - 37980571

AN - SCOPUS:85177188374

SN - 2211-1247

VL - 42

SP - 113446

JO - Cell Reports

JF - Cell Reports

IS - 11

M1 - 113446

ER -

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

Abstract

Funding

Research Areas and Centers

DFG Research Classification Scheme

UN SDGs

Access to Document

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