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

Jeanette A. Johansson; K.L. Marie; Yuting Lu; Alessandro Brombin; Cristina Santoriello; Zhiqiang Zeng; Judith Zich; Philippe Gautier; Alexander 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

Jeanette A. Johansson, K.L. Marie, Yuting Lu, Alessandro Brombin, Cristina Santoriello, Zhiqiang Zeng, Judith Zich, Philippe Gautier, Alexander 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

Division of Molecular & Cellular Function (L5)

University of Edinburgh

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 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.

Original language	English
Pages (from-to)	317-332.E9
Number of pages	26
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

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Johansson, J. A., 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. S., & 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

@article{c5823461f0e64079aff61b7c7bd5e475,

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 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.",

author = "Johansson, {Jeanette A.} and K.L. Marie and Yuting Lu and Alessandro Brombin and Cristina Santoriello and Zhiqiang Zeng and Judith Zich and Philippe Gautier and {von Kriegsheim}, Alexander 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 Illingworth, {Robert S.} 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",

publisher = "Cell Press",

number = "3",

}

Johansson, JA, 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, RS & 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 A.

AU - Marie, K.L.

AU - Lu, Yuting

AU - Brombin, Alessandro

AU - Santoriello, Cristina

AU - Zeng, Zhiqiang

AU - Zich, Judith

AU - Gautier, Philippe

AU - von Kriegsheim, Alexander

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 S.

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 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.

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 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.

UR - http://dx.doi.org/10.1016/j.devcel.2020.06.013

U2 - 10.1016/j.devcel.2020.06.013

DO - 10.1016/j.devcel.2020.06.013

M3 - Article

SN - 1534-5807

VL - 54

SP - 317-332.E9

JO - Developmental cell

JF - Developmental cell

IS - 3

ER -

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

Abstract

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