PRL3-DDX21 transcriptional control of endolysosomal genes restricts melanocyte stem cell differentiation

Jeanette Johansson; Kerrie L. Marie; Yuting Lu; Alessandro Brombin; Cristina Santoriello; Zhiqiang Zeng; Judith Zich; Phillipe 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 Illingworth; E Elizabeth Patton

doi:10.1016/j.devcel.2020.06.013

PRL3-DDX21 transcriptional control of endolysosomal genes restricts melanocyte stem cell differentiation

Jeanette Johansson, Kerrie L. Marie, Yuting Lu, Alessandro Brombin, Cristina Santoriello, Zhiqiang Zeng, Judith Zich, Phillipe 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 Illingworth, E Elizabeth Patton

Research output: Contribution to journal › Article › peer-review

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 melanocyte stem cell regeneration. We show that PRL3 binds to the RNA helicase DDX21, thereby restricting productive transcription by RNAPII at 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.

Original language	English
Pages (from-to)	317-332.E9
Number of pages	16
Journal	Developmental Cell
Volume	54
Issue number	3
Early online date	10 Jul 2020
DOIs	https://doi.org/10.1016/j.devcel.2020.06.013
Publication status	Published - 10 Aug 2020

Keywords

zebrafish
melanocyte stem cell
small molecule screen
regeneration
PRL3
PTP4A3
transcription elongation
MITF
DDX21
melanoma

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PattonEtalDC2020PRL3-DDX21TranscriptionalControlFinal published version, 12.6 MBLicence: Creative Commons: Attribution (CC-BY)

1 Active
2 Finished

Cell-Specific PRC1 Accessory Proteins and the Regulation of Mammalian Neurodevelopment
Illingworth, R.
MRC
1/04/19 → 31/03/24
Project: Research
Gene-drug interactions in the melanocyte lineage and melanoma
Patton, E.
1/04/18 → 31/03/23
Project: Research
Chemical Biology in Zebrafish: Drug-Leads and New Targets
Patton, E.
EU government bodies
1/09/15 → 28/02/22
Project: Research

Cite this

Johansson, J., Marie, K. L., Lu, Y., Brombin, A., Santoriello, C., Zeng, Z., Zich, J., Gautier, P., von Kriegsheim, A., Brunsdon, H., Wheeler, A. P., Dreger, M., Houston, D. R., Dooley, C. M., Sims, A. H., Busch-Nentwich, E. M., Zon, L. I., Illingworth, R., & Patton, E. E. (2020). PRL3-DDX21 transcriptional control of endolysosomal genes restricts melanocyte stem cell differentiation. Developmental Cell, 54(3), 317-332.E9. https://doi.org/10.1016/j.devcel.2020.06.013

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title = "PRL3-DDX21 transcriptional control of endolysosomal genes restricts melanocyte stem cell differentiation",

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 melanocyte stem cell regeneration. We show that PRL3 binds to the RNA helicase DDX21, thereby restricting productive transcription by RNAPII at 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 = "zebrafish, melanocyte stem cell, small molecule screen, regeneration, PRL3, PTP4A3, transcription elongation, MITF, DDX21, melanoma",

author = "Jeanette Johansson and Marie, {Kerrie L.} and Yuting Lu and Alessandro Brombin and Cristina Santoriello and Zhiqiang Zeng and Judith Zich and Phillipe Gautier and {von Kriegsheim}, Alex and Hannah Brunsdon and Wheeler, {Ann P} and Marcel Dreger and Houston, {Douglas R} and Dooley, {Christopher M.} and Sims, {Andrew H} and Busch-Nentwich, {Elisabeth M} and Zon, {Leonard I} and Robert Illingworth and Patton, {E Elizabeth}",

year = "2020",

month = aug,

day = "10",

doi = "10.1016/j.devcel.2020.06.013",

language = "English",

volume = "54",

pages = "317--332.E9",

journal = "Developmental Cell",

issn = "1534-5807",

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Johansson, J, Marie, KL, Lu, Y, Brombin, A, Santoriello, C, Zeng, Z, Zich, J, Gautier, P, von Kriegsheim, A , Brunsdon, H , Wheeler, AP, Dreger, M, Houston, DR, Dooley, CM, Sims, AH, Busch-Nentwich, EM, Zon, LI, Illingworth, R & Patton, EE 2020, 'PRL3-DDX21 transcriptional control of endolysosomal genes restricts melanocyte stem cell differentiation', Developmental Cell, vol. 54, no. 3, pp. 317-332.E9. https://doi.org/10.1016/j.devcel.2020.06.013

TY - JOUR

T1 - PRL3-DDX21 transcriptional control of endolysosomal genes restricts melanocyte stem cell differentiation

AU - Johansson, Jeanette

AU - Marie, Kerrie L.

AU - Lu, Yuting

AU - Brombin, Alessandro

AU - Santoriello, Cristina

AU - Zeng, Zhiqiang

AU - Zich, Judith

AU - Gautier, Phillipe

AU - von Kriegsheim, Alex

AU - Brunsdon, Hannah

AU - Wheeler, Ann P

AU - Dreger, Marcel

AU - Houston, Douglas R

AU - Dooley, Christopher M.

AU - Sims, Andrew H

AU - Busch-Nentwich, Elisabeth M

AU - Zon, Leonard I

AU - Illingworth, Robert

AU - Patton, E Elizabeth

PY - 2020/8/10

Y1 - 2020/8/10

N2 - 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 melanocyte stem cell regeneration. We show that PRL3 binds to the RNA helicase DDX21, thereby restricting productive transcription by RNAPII at 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.

AB - 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 melanocyte stem cell regeneration. We show that PRL3 binds to the RNA helicase DDX21, thereby restricting productive transcription by RNAPII at 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.

KW - zebrafish

KW - melanocyte stem cell

KW - small molecule screen

KW - regeneration

KW - PRL3

KW - PTP4A3

KW - transcription elongation

KW - MITF

KW - DDX21

KW - melanoma

U2 - 10.1016/j.devcel.2020.06.013

DO - 10.1016/j.devcel.2020.06.013

M3 - Article

VL - 54

SP - 317-332.E9

JO - Developmental Cell

JF - Developmental Cell

SN - 1534-5807

IS - 3

ER -

PRL3-DDX21 transcriptional control of endolysosomal genes restricts melanocyte stem cell differentiation

Abstract

Keywords

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Projects

Cell-Specific PRC1 Accessory Proteins and the Regulation of Mammalian Neurodevelopment

Gene-drug interactions in the melanocyte lineage and melanoma

Chemical Biology in Zebrafish: Drug-Leads and New Targets

Cite this