N6-methyladenosine mRNA marking promotes selective translation of regulons required for human erythropoiesis

Daniel A. Kuppers, Sonali Arora, Yiting Lim, Andrea R. Lim, Lucas M. Carter, Philip D. Corrin, Christopher L. Plaisier, Ryan Basom, Jeffrey J. Delrow, Shiyan Wang, Housheng Hansen He, Beverly Torok-Storb, Andrew C. Hsieh, Patrick J. Paddison

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Many of the regulatory features governing erythrocyte specification, maturation, and associated disorders remain enigmatic. To identify new regulators of erythropoiesis, we utilize a functional genomic screen for genes affecting expression of the erythroid marker CD235a/GYPA. Among validating hits are genes coding for the N6-methyladenosine (m6A) mRNA methyltransferase (MTase) complex, including, METTL14, METTL3, and WTAP. We demonstrate that m6A MTase activity promotes erythroid gene expression programs through selective translation of ~300 m6A marked mRNAs, including those coding for SETD histone methyltransferases, ribosomal components, and polyA RNA binding proteins. Remarkably, loss of m6A marks results in dramatic loss of H3K4me3 marks across key erythroid-specific KLF1 transcriptional targets (e.g., Heme biosynthesis genes). Further, each m6A MTase subunit and a subset of their mRNAs targets are required for human erythroid specification in primary bone-marrow derived progenitors. Thus, m6A mRNA marks promote the translation of a network of genes required for human erythropoiesis.

Original languageEnglish (US)
Article number4596
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

Fingerprint

Regulon
Erythropoiesis
genes
marking
Genes
gene expression
Methyltransferases
Gene expression
Messenger RNA
specifications
coding
Specifications
Gene Expression
biosynthesis
RNA-Binding Proteins
bone marrow
Gene Regulatory Networks
Biosynthesis
regulators
erythrocytes

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Kuppers, D. A., Arora, S., Lim, Y., Lim, A. R., Carter, L. M., Corrin, P. D., ... Paddison, P. J. (2019). N6-methyladenosine mRNA marking promotes selective translation of regulons required for human erythropoiesis. Nature communications, 10(1), [4596]. https://doi.org/10.1038/s41467-019-12518-6

N6-methyladenosine mRNA marking promotes selective translation of regulons required for human erythropoiesis. / Kuppers, Daniel A.; Arora, Sonali; Lim, Yiting; Lim, Andrea R.; Carter, Lucas M.; Corrin, Philip D.; Plaisier, Christopher L.; Basom, Ryan; Delrow, Jeffrey J.; Wang, Shiyan; Hansen He, Housheng; Torok-Storb, Beverly; Hsieh, Andrew C.; Paddison, Patrick J.

In: Nature communications, Vol. 10, No. 1, 4596, 01.12.2019.

Research output: Contribution to journalArticle

Kuppers, DA, Arora, S, Lim, Y, Lim, AR, Carter, LM, Corrin, PD, Plaisier, CL, Basom, R, Delrow, JJ, Wang, S, Hansen He, H, Torok-Storb, B, Hsieh, AC & Paddison, PJ 2019, 'N6-methyladenosine mRNA marking promotes selective translation of regulons required for human erythropoiesis', Nature communications, vol. 10, no. 1, 4596. https://doi.org/10.1038/s41467-019-12518-6
Kuppers, Daniel A. ; Arora, Sonali ; Lim, Yiting ; Lim, Andrea R. ; Carter, Lucas M. ; Corrin, Philip D. ; Plaisier, Christopher L. ; Basom, Ryan ; Delrow, Jeffrey J. ; Wang, Shiyan ; Hansen He, Housheng ; Torok-Storb, Beverly ; Hsieh, Andrew C. ; Paddison, Patrick J. / N6-methyladenosine mRNA marking promotes selective translation of regulons required for human erythropoiesis. In: Nature communications. 2019 ; Vol. 10, No. 1.
@article{0c12a866c75848f4a65a0cd56bec9a5a,
title = "N6-methyladenosine mRNA marking promotes selective translation of regulons required for human erythropoiesis",
abstract = "Many of the regulatory features governing erythrocyte specification, maturation, and associated disorders remain enigmatic. To identify new regulators of erythropoiesis, we utilize a functional genomic screen for genes affecting expression of the erythroid marker CD235a/GYPA. Among validating hits are genes coding for the N6-methyladenosine (m6A) mRNA methyltransferase (MTase) complex, including, METTL14, METTL3, and WTAP. We demonstrate that m6A MTase activity promotes erythroid gene expression programs through selective translation of ~300 m6A marked mRNAs, including those coding for SETD histone methyltransferases, ribosomal components, and polyA RNA binding proteins. Remarkably, loss of m6A marks results in dramatic loss of H3K4me3 marks across key erythroid-specific KLF1 transcriptional targets (e.g., Heme biosynthesis genes). Further, each m6A MTase subunit and a subset of their mRNAs targets are required for human erythroid specification in primary bone-marrow derived progenitors. Thus, m6A mRNA marks promote the translation of a network of genes required for human erythropoiesis.",
author = "Kuppers, {Daniel A.} and Sonali Arora and Yiting Lim and Lim, {Andrea R.} and Carter, {Lucas M.} and Corrin, {Philip D.} and Plaisier, {Christopher L.} and Ryan Basom and Delrow, {Jeffrey J.} and Shiyan Wang and {Hansen He}, Housheng and Beverly Torok-Storb and Hsieh, {Andrew C.} and Paddison, {Patrick J.}",
year = "2019",
month = "12",
day = "1",
doi = "10.1038/s41467-019-12518-6",
language = "English (US)",
volume = "10",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",

}

TY - JOUR

T1 - N6-methyladenosine mRNA marking promotes selective translation of regulons required for human erythropoiesis

AU - Kuppers, Daniel A.

AU - Arora, Sonali

AU - Lim, Yiting

AU - Lim, Andrea R.

AU - Carter, Lucas M.

AU - Corrin, Philip D.

AU - Plaisier, Christopher L.

AU - Basom, Ryan

AU - Delrow, Jeffrey J.

AU - Wang, Shiyan

AU - Hansen He, Housheng

AU - Torok-Storb, Beverly

AU - Hsieh, Andrew C.

AU - Paddison, Patrick J.

PY - 2019/12/1

Y1 - 2019/12/1

N2 - Many of the regulatory features governing erythrocyte specification, maturation, and associated disorders remain enigmatic. To identify new regulators of erythropoiesis, we utilize a functional genomic screen for genes affecting expression of the erythroid marker CD235a/GYPA. Among validating hits are genes coding for the N6-methyladenosine (m6A) mRNA methyltransferase (MTase) complex, including, METTL14, METTL3, and WTAP. We demonstrate that m6A MTase activity promotes erythroid gene expression programs through selective translation of ~300 m6A marked mRNAs, including those coding for SETD histone methyltransferases, ribosomal components, and polyA RNA binding proteins. Remarkably, loss of m6A marks results in dramatic loss of H3K4me3 marks across key erythroid-specific KLF1 transcriptional targets (e.g., Heme biosynthesis genes). Further, each m6A MTase subunit and a subset of their mRNAs targets are required for human erythroid specification in primary bone-marrow derived progenitors. Thus, m6A mRNA marks promote the translation of a network of genes required for human erythropoiesis.

AB - Many of the regulatory features governing erythrocyte specification, maturation, and associated disorders remain enigmatic. To identify new regulators of erythropoiesis, we utilize a functional genomic screen for genes affecting expression of the erythroid marker CD235a/GYPA. Among validating hits are genes coding for the N6-methyladenosine (m6A) mRNA methyltransferase (MTase) complex, including, METTL14, METTL3, and WTAP. We demonstrate that m6A MTase activity promotes erythroid gene expression programs through selective translation of ~300 m6A marked mRNAs, including those coding for SETD histone methyltransferases, ribosomal components, and polyA RNA binding proteins. Remarkably, loss of m6A marks results in dramatic loss of H3K4me3 marks across key erythroid-specific KLF1 transcriptional targets (e.g., Heme biosynthesis genes). Further, each m6A MTase subunit and a subset of their mRNAs targets are required for human erythroid specification in primary bone-marrow derived progenitors. Thus, m6A mRNA marks promote the translation of a network of genes required for human erythropoiesis.

UR - http://www.scopus.com/inward/record.url?scp=85073112819&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85073112819&partnerID=8YFLogxK

U2 - 10.1038/s41467-019-12518-6

DO - 10.1038/s41467-019-12518-6

M3 - Article

C2 - 31601799

AN - SCOPUS:85073112819

VL - 10

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 4596

ER -