PRL3-DDX21 Transcriptional Control of Endolysosomal Genes Restricts Melanocyte Stem Cell Differentiation

Jeanette A Johansson; Kerrie L Marie; Yuting Lu; Alessandro Brombin; Cristina Santoriello; Zhiqiang Zeng; Judith Zich; Philippe Gautier; Alex von Kriegsheim; Hannah Brunsdon; Ann P Wheeler; Marcel Dreger; Douglas R Houston; Christopher M Dooley; Andrew H Sims; Elisabeth M Busch-Nentwich; Leonard I Zon; Robert S Illingworth; E Elizabeth Patton

doi:10.1016/j.devcel.2020.06.013

PRL3-DDX21 Transcriptional Control of Endolysosomal Genes Restricts Melanocyte Stem Cell Differentiation

Dev Cell. 2020 Aug 10;54(3):317-332.e9. doi: 10.1016/j.devcel.2020.06.013. Epub 2020 Jul 10.

Authors

Jeanette A Johansson¹, Kerrie L Marie², Yuting Lu¹, Alessandro Brombin¹, Cristina Santoriello³, Zhiqiang Zeng¹, Judith Zich¹, Philippe Gautier⁴, Alex von Kriegsheim⁵, Hannah Brunsdon¹, Ann P Wheeler⁴, Marcel Dreger¹, Douglas R Houston⁶, Christopher M Dooley⁷, Andrew H Sims⁵, Elisabeth M Busch-Nentwich⁸, Leonard I Zon³, Robert S Illingworth⁹, E Elizabeth Patton¹⁰

Affiliations

¹ MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh EH4 2XU, UK; Cancer Research UK Edinburgh Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
² MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh EH4 2XU, UK; Cancer Research UK Edinburgh Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK; Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
³ Stem Cell Program and Division of Hematology, Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Medical School, Harvard Stem Cell Institute, Stem Cell and Regenerative Biology Department, Harvard University, Boston, USA.
⁴ MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh EH4 2XU, UK.
⁵ Cancer Research UK Edinburgh Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
⁶ Institute of Quantitative Biology, Biochemistry and Biotechnology, Waddington Building, King's Buildings, University of Edinburgh, Edinburgh EH9 3BF, UK.
⁷ Wellcome Sanger Institute, Hinxton CB10 1SA, UK; Max-Planck-Institute for Developmental Biology, Department ECNV, Max-Planck-Ring 5, 72076 Tübingen, Germany.
⁸ Wellcome Sanger Institute, Hinxton CB10 1SA, UK; Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Jeffrey Cheah Biomedical Centre, University of Cambridge, Puddicombe Way, Cambridge CB2 0AW, UK.
⁹ Centre for Regenerative Medicine, Institute for Regeneration and Repair, The University of Edinburgh, Edinburgh BioQuarter, 5 Little France Drive, Edinburgh EH16 4UU, UK. Electronic address: [email protected].
¹⁰ MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh EH4 2XU, UK; Cancer Research UK Edinburgh Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK. Electronic address: [email protected].

Abstract

Melanocytes, replenished throughout life by melanocyte stem cells (MSCs), play a critical role in pigmentation and melanoma. Here, we reveal a function for the metastasis-associated phosphatase of regenerating liver 3 (PRL3) in MSC regeneration. We show that PRL3 binds to the RNA helicase DDX21, thereby restricting productive transcription by RNAPII at master transcription factor (MITF)-regulated endolysosomal vesicle genes. In zebrafish, this mechanism controls premature melanoblast expansion and differentiation from MSCs. In melanoma patients, restricted transcription of this endolysosomal vesicle pathway is a hallmark of PRL3-high melanomas. Our work presents the conceptual advance that PRL3-mediated control of transcriptional elongation is a differentiation checkpoint mechanism for activated MSCs and has clinical relevance for the activity of PRL3 in regenerating tissue and cancer.

Keywords: DDX21; MITF; PRL3; PTP4A3; melanocyte stem cell; melanoma; regeneration; small-molecule screen; transcription elongation; zebrafish.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation / genetics*
DEAD-box RNA Helicases / genetics
DEAD-box RNA Helicases / metabolism*
Gene Expression Regulation, Developmental
Humans
Melanocytes / cytology*
Melanoma / genetics
Melanoma / metabolism*
Microphthalmia-Associated Transcription Factor / genetics
Mutation
Neoplasm Proteins / genetics
Neoplasm Proteins / metabolism*
Protein Tyrosine Phosphatases / genetics
Protein Tyrosine Phosphatases / metabolism*
Stem Cells / metabolism
Zebrafish / metabolism
Zebrafish Proteins / metabolism

Substances

Microphthalmia-Associated Transcription Factor
Neoplasm Proteins
Zebrafish Proteins
PTP4A3 protein, human
Protein Tyrosine Phosphatases
DDX21 protein, human
DEAD-box RNA Helicases

Abstract

Publication types

MeSH terms

Substances

Grants and funding