​Blood Qian Zhijian/He Chuan cooperate to analyze the new mechanism of YTHDC1 in hematopoiesis and leukemia development

N6-methyladenosine (m6A) modification is one of the most abundant modifications on eukaryotic mRNA.
It regulates the metabolic fate of mRNA, including stabilization, degradation, localization, and splicing
.

RNA m6A modification is a dynamic and reversible regulatory process, which will be written by the methyltransferase complex (writer) METL3, METL14, WTAP, RAB15/15B, and erased by the demethylase (eraser) ALKBH5, FTO protein
.

There are many readers in eukaryotic cells that can specifically recognize m6A modifications, such as YTHDF1/2/3, YTHDC1/2, etc.
, which determine the fate of their target genes by recognizing m6A modifications on RNA
.

In recent years, studies have found that m6A-modified related proteins are involved in the regulation of many biological processes such as development, immunity, and differentiation, and also play an important role in the occurrence and development of cancer.
This has led the Sina of RNA epigenetics research Tide
.

At present, studies have reported in detail that some related proteins of m6A participate in the regulation of hematopoiesis and the development of leukemia, including writer MTETTL3 [1], METTL14 [2]; eraser FTO [3], ALKBH5 [4]; reader YTHDF2 [5], etc.

.

However, it is not clear whether YTHDC1, as the only YTH family protein located in the nucleus, can participate in hematopoiesis and the pathogenesis of leukemia
.

On July 13, 2021, Professor Qian Zhijian’s team from the University of Florida, in conjunction with Professor He Chuan’s team from the University of Chicago, published an article A Critical Role of Nuclear m6A Reader YTHDC1 in Leukemogenesis by Regulating MCM Complex-Mediated DNA Replication in Blood, using in vivo for the first time The experiment revealed the important role of YTHDC1 protein involved in normal hematopoiesis and the development of leukemia and related molecular mechanisms
.

Researchers first started with a database of patients with acute myeloid leukemia (AML) and found that YTHDC1 was significantly highly expressed in a variety of different karyotypes of AML
.

Researchers used shRNA to knock down the expression level of YTHDC1 in a variety of AML cell lines, and found that YTHDC1 knockdown significantly inhibited the growth of AML cells and increased their apoptosis and differentiation
.

Subsequently, the research team constructed a variety of AML models of Ythdc1 knockout mice, and found that knocking out Ythdc1 can significantly inhibit the growth of AML cells in mice and inhibit the function of leukemia stem cells, thereby prolonging the survival time of AML mice
.

Further studies have found that inhibiting the expression of YTHDC1 in primary AML patient cells and stem progenitor cells (CD34+) derived from healthy people can significantly and specifically inhibit the growth of AML cells, but has little effect on CD34+
.

So is Ythdc1 involved in hematopoietic development and the regulation of hematopoietic stem cells (HSC)? After the researchers knocked out Ythdc1, the mice all died within 3 weeks, and the number of various mature cells decreased significantly.
Hematopoietic stem cells were almost undetectable, showing a typical phenotype of acute bone marrow failure (Bone Marrow Failure)
.

Bone marrow competition experiments showed that Ythdc1 knockout resulted in a significant decrease in HSC function
.

Interestingly, compared to Mettl3 knockout mice [6], the phenotype caused by Ythdc1 knockout is more pronounced.
These data suggest that Ythdc1 may have a non-m6A-dependent function in HSC
.

Mechanism studies have shown that YTHDC1 can regulate multiple genes involved in DNA replication and chromosome regulation, including MCM2/4/5 and RFC1
.

Among them, MCM4 is also highly expressed in a variety of AML, and is significantly positively correlated with the expression level of YTHDC1
.

YTHDC1 recognizes the m6A modification on MCM4 and binds to MCM4 to stabilize its mRNA
.

Re-expression of MCM4 can significantly restore growth inhibition, apoptosis and increased differentiation caused by YTHDC1 deletion
.

DNA fiber experiments show that inhibiting the expression of YTHDC1 can significantly inhibit the DNA replication process, the length of a single DNA molecule replication fiber is significantly shortened, and the re-expression of MCM4 can restore the DNA replication process, which indicates that YTHDC1 mainly mediates the regulation of DNA replication through MCM4
.

What’s more interesting is that YTHDC1 regulates cell transcription through carRNA [7], transposon [8], chromatin modification [9], etc.
, as has been reported so far, and regulates mRNA alternative splicing [10], subcellular localization [ 11].
The difference between waiting to regulate downstream target gene expression is that Qian Zhijian’s research team discovered for the first time that YTHDC1 can regulate its fate by specifically binding m6A-modified mRNA to stabilize it, which is different from the reported functions of YTHDC1.

.

In summary, this study clarified the important role of YTHDC1 in the occurrence of normal hematopoiesis and leukemia, and thoroughly studied the effect of Ythdc1 deficiency on the function of hematopoietic stem cells and leukemia stem cells
.

It is worth mentioning that recently, Dr.
Cheng Yuanming/Dr.
Xie Wei of the Michael G Kharas team also wrote an article to clarify the important role of YTHDC1 in AML (for details, see BioArt report: Cancer Cell | Cheng Yuanming/Xie Wei et al.
Reveal the passage of m⁶A reading protein YTHDC1 in the nucleus The mechanism by which phase separation regulates gene expression and promotes the development of AML)
.

But the mechanism is different
.

Qian Zhijian/He Chuan's group pointed out that MCM4 is an important downstream of YTHDC1, while Michael G Kharas's group found that YTHDC1 regulates the stability of c-Myc mRNA through phase separation [12]
.

As a key factor, c-Myc mediates the functions of multiple m6A-related proteins in AML [13]
.

Recently, Qian Zhijian’s research team used a variety of in vivo models to clarify the important role of c-Myc in the regulation of normal hematopoietic and hematopoietic stem cell functions, as well as its functional heterogeneity in the bone marrow microenvironment
.

The article was published in Blood on February 4, 2021
.

Previously, it was reported that the complete lack of c-Myc would cause HSC accumulation and differentiation, but the cell cycle and apoptosis did not change [14]
.

Research by Qian Zhijian’s research group found that c-Myc haplotype insufficiency caused a completely different phenotype.
HSC differentiation was normal, but the stationary phase (G0) was significantly reduced, apoptosis increased, and self-renewal ability was significantly reduced [15]
.

This part of the research work further supports that the effect of Ythdc1 deletion on hematopoietic stem cell function may also be partly through the regulation of the stability of c-Myc mRNA
.

The YTHDC1 project is co-corresponding by Professor Qian Zhijian from the University of Florida and Professor He Chuan from the University of Chicago, and Dr.
Sheng Yue and Dr.
Wei Jiangbo are the co-first authors
.

Yu Fang, Xu Huanzhou, Yu Chunjie, and Dr.
Liu Yin all made important contributions
.

The work on the c-Myc project is led by Professor Qian Zhijian from the University of Florida as the corresponding author, and Dr.
Sheng Yue is the first author
.

Ma Rui, Yu Spring Festival, etc.
have all made important contributions
.

Original link: https://ashpublications.
org/blood/article-abstract/doi/10.
1182/blood.
2021011707/476382/A-Critical-Role-of-Nuclear-m6A-Reader-YTHDC1-in?redirectedFrom=fulltext Recruitment: There are currently many postdoctoral vacancies in the Qian Zhijian research group of the University of Florida.
The research direction is the epigenetic regulation of DNA/RNA, the role of protein translation and post-translational modification in the occurrence of normal hematopoiesis and leukemia, and new drugs Development
.

Recently published articles include: Blood, Nature Communication, Cell stem Cell, Cancer Cell, Nature Immunology and so on
.

For more information, please visit the lab homepage: https://directory.
ufhealth.
org/qian-zhijian Introduction to the first author: Dr.
Sheng Yue, a research assistant professor at the University of Florida, graduated from the School of Life Sciences, Wuhan University, afterwards Professor Yu Qian Zhijian’s research group conducts post-doctoral training
.

In recent years, I have published many research papers in related fields as the first author (including co-authors), including: Blood (2021a, 2021b), Cell Stem Cell (2020), Nature Communications (2020), Cancer Cell (2019), Molecular Cancer (2019) ), Cell Death & Differentiation (2018 ), Cancer Research (2017), Leukemia (2016) and the like
.

Now relying on the preparation of the research group of the Department of Hematology of the Second Xiangya Hospital, it recruits many post-doctoral, doctoral and master students
.

Resume delivery (for those who are interested, please send your resume and other materials to): https://jinshuju.
net/f/ZqXwZt or scan the QR code to deliver your resume.
Platemaker: Eleven References 1.
Vu LP, Pickering BF, Cheng Y, et al.
The N(6)-methyladenosine (m(6)A)-forming enzyme METTL3 controls myeloid differentiation of normal hematopoietic and leukemia cells.
Nat Med.
2017;23(11):1369-1376.
2.
Weng H , Huang H, Wu H, et al.
METTL14 Inhibits Hematopoietic Stem/Progenitor Differentiation and Promotes Leukemogenesis via mRNA m(6)A Modification.
Cell Stem Cell.
2017.
3.
Li Z, Weng H, Su R, et al.
FTO Plays an Oncogenic Role in Acute Myeloid Leukemia as a N6-Methyladenosine RNA Demethylase.
Cancer Cell.
2016.
4.
Su R, Dong L, Li Y, et al.
Targeting FTO Suppresses Cancer Stem Cell Maintenance and Immune Evasion.
Cancer Cell.
2020;38(1 ):79-96 e11.
5.
Paris J, Morgan M, Campos J, et al.
Targeting the RNA m(6)A Reader YTHDF2 Selectively Compromises Cancer Stem Cells in Acute Myeloid Leukemia.
Cell Stem Cell.
2019;25(1):137-148 e136.
6.
Cheng Y, Luo H, Izzo F, et al.
m(6)A RNA Methylation Maintains Hematopoietic Stem Cell Identity and Symmetric Commitment.
Cell Rep.
2019;28(7):1703-1716 e1706.
7.
Liu J, Dou X, Chen C, et al.
N (6)- methyladenosine of chromosome-associated regulatory RNA regulates chromatin state and transcription.
Science.
2020;367(6477):580-586.
8.
Liu J, Gao M, He J, et al.
The RNA m(6)A reader YTHDC1 silences retrotransposons and guards ES cell identity.
Nature.
2021;591(7849):322-326.
9.
Li Y, Xia L, Tan K, et al.
N(6)-Methyladenosine co-transcriptionally directs the demethylation of histone H3K9me2.
Nat Genet.
2020.
10 .
Xiao W, Adhikari S, Dahal U, et al.
Nuclear m(6)A Reader YTHDC1 Regulates mRNA Splicing.
Mol Cell.
2016;61(4):507-519.
11.
Roundtree IA, Luo GZ, Zhang Z, et al.
YTHDC1 mediates nuclear export of N(6)-methyladenosine methylated mRNAs.
eLife.
2017;6.
12.
Cheng Y, Xie W, Pickering BF, et al.
N(6)-Methyladenosine on mRNA facilitates a phase-separated nuclear body that suppresses myeloid leukemic differentiation.
Cancer Cell.
2021.
13.
Qing Y, Su R, Chen J.
RNA modifications in hematopoietic malignancies: A new research frontier.
Blood.
2021.
14.
Wilson A, Murphy MJ, Oskarsson T, et al.
c-Myc controls the balance between hematopoietic stem cell self-renewal and differentiation.
Genes Dev.
2004;18(22):2747-2763.
15.
Sheng Y, Ma R, Yu C, et al.
Role of c-Myc haploinsufficiency in the maintenance of HSCs in mice.
Blood.
2021;137(5):610-623.
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Luo GZ, Zhang Z, et al.
YTHDC1 mediates nuclear export of N(6)-methyladenosine methylated mRNAs.
eLife.
2017;6.
12.
Cheng Y, Xie W, Pickering BF, et al.
N(6)-Methyladenosine on mRNA facilitates a phase-separated nuclear body that suppresses myeloid leukemic differentiation.
Cancer Cell.
2021.
13.
Qing Y, Su R, Chen J.
RNA modifications in hematopoietic malignancies: A new research frontier.
Blood.
2021.
14.
Wilson A, Murphy MJ, Oskarsson T, et al.
c-Myc controls the balance between hematopoietic stem cell self-renewal and differentiation.
Genes Dev.
2004;18(22):2747-2763.
15.
Sheng Y, Ma R, Yu C, et al.
Role of c-Myc haploinsufficiency in the maintenance of HSCs in mice.
Blood.
2021;137(5):610-623.
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Personal forwarding and sharing are welcome, without permission Reprinting is prohibited, the author has all legal rights, offenders must be investigatedLuo GZ, Zhang Z, et al.
YTHDC1 mediates nuclear export of N(6)-methyladenosine methylated mRNAs.
eLife.
2017;6.
12.
Cheng Y, Xie W, Pickering BF, et al.
N(6)-Methyladenosine on mRNA facilitates a phase-separated nuclear body that suppresses myeloid leukemic differentiation.
Cancer Cell.
2021.
13.
Qing Y, Su R, Chen J.
RNA modifications in hematopoietic malignancies: A new research frontier.
Blood.
2021.
14.
Wilson A, Murphy MJ, Oskarsson T, et al.
c-Myc controls the balance between hematopoietic stem cell self-renewal and differentiation.
Genes Dev.
2004;18(22):2747-2763.
15.
Sheng Y, Ma R, Yu C, et al.
Role of c-Myc haploinsufficiency in the maintenance of HSCs in mice.
Blood.
2021;137(5):610-623.
(Swipe up and down to read) Instructions for reprinting [Non-original articles] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome, without permission Reprinting is prohibited, the author has all legal rights, offenders must be investigatedYTHDC1 mediates nuclear export of N(6)-methyladenosine methylated mRNAs.
eLife.
2017;6.
12.
Cheng Y, Xie W, Pickering BF, et al.
N(6)-Methyladenosine on mRNA facilitates a phase-separated nuclear body that suppresses myeloid leukemic differentiation.
Cancer Cell.
2021.
13.
Qing Y, Su R, Chen J.
RNA modifications in hematopoietic malignancies: A new research frontier.
Blood.
2021.
14.
Wilson A, Murphy MJ, Oskarsson T, et al.
c-Myc controls the balance between hematopoietic stem cell self-renewal and differentiation.
Genes Dev.
2004;18(22):2747-2763.
15.
Sheng Y, Ma R, Yu C, et al.
Role of c-Myc haploinsufficiency in the maintenance of HSCs in mice.
Blood.
2021;137(5):610-623.
(Swipe up and down to read) Reprinting instructions [Non-original articles] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is prohibited without permission.
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Offenders must be investigatedYTHDC1 mediates nuclear export of N(6)-methyladenosine methylated mRNAs.
eLife.
2017;6.
12.
Cheng Y, Xie W, Pickering BF, et al.
N(6)-Methyladenosine on mRNA facilitates a phase-separated nuclear body that suppresses myeloid leukemic differentiation.
Cancer Cell.
2021.
13.
Qing Y, Su R, Chen J.
RNA modifications in hematopoietic malignancies: A new research frontier.
Blood.
2021.
14.
Wilson A, Murphy MJ, Oskarsson T, et al.
c-Myc controls the balance between hematopoietic stem cell self-renewal and differentiation.
Genes Dev.
2004;18(22):2747-2763.
15.
Sheng Y, Ma R, Yu C, et al.
Role of c-Myc haploinsufficiency in the maintenance of HSCs in mice.
Blood.
2021;137(5):610-623.
(Swipe up and down to read) Reprinting instructions [Non-original articles] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is prohibited without permission.
The author has all legal rights.
Offenders must be investigatedN(6)-Methyladenosine on mRNA facilitates a phase-separated nuclear body that suppresses myeloid leukemic differentiation.
Cancer Cell.
2021.
13.
Qing Y, Su R, Chen J.
RNA modifications in hematopoietic malignancies: A new research frontier.
Blood.
2021.
14.
Wilson A, Murphy MJ, Oskarsson T, et al.
c-Myc controls the balance between hematopoietic stem cell self-renewal and differentiation.
Genes Dev.
2004;18(22):2747-2763.
15.
Sheng Y, Ma R, Yu C , et al.
Role of c-Myc haploinsufficiency in the maintenance of HSCs in mice.
Blood.
2021;137(5):610-623.
(Swipe up and down to read) Reprint Instructions [Non-original article] The copyright of this article belongs to the author of the article , Welcome personal reposting and sharing, reprinting is prohibited without permission, the author has all legal rights, offenders must be investigatedN(6)-Methyladenosine on mRNA facilitates a phase-separated nuclear body that suppresses myeloid leukemic differentiation.
Cancer Cell.
2021.
13.
Qing Y, Su R, Chen J.
RNA modifications in hematopoietic malignancies: A new research frontier.
Blood.
2021.
14.
Wilson A, Murphy MJ, Oskarsson T, et al.
c-Myc controls the balance between hematopoietic stem cell self-renewal and differentiation.
Genes Dev.
2004;18(22):2747-2763.
15.
Sheng Y, Ma R, Yu C , et al.
Role of c-Myc haploinsufficiency in the maintenance of HSCs in mice.
Blood.
2021;137(5):610-623.
(Swipe up and down to read) Reprint Instructions [Non-original article] The copyright of this article belongs to the author of the article , Welcome personal reposting and sharing, reprinting is prohibited without permission, the author has all legal rights, offenders must be investigatedc-Myc controls the balance between hematopoietic stem cell self-renewal and differentiation.
Genes Dev.
2004;18(22):2747-2763.
15.
Sheng Y, Ma R, Yu C, et al.
Role of c-Myc haploinsufficiency in the maintenance of HSCs in mice.
Blood.
2021;137(5):610-623.
(Swipe up and down to read) Reprint Instructions [Non-original articles] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is prohibited without permission.
The author has all legal rights, and offenders must be investigatedc-Myc controls the balance between hematopoietic stem cell self-renewal and differentiation.
Genes Dev.
2004;18(22):2747-2763.
15.
Sheng Y, Ma R, Yu C, et al.
Role of c-Myc haploinsufficiency in the maintenance of HSCs in mice.
Blood.
2021;137(5):610-623.
(Swipe up and down to read) Reprint Instructions [Non-original articles] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is prohibited without permission.
The author has all legal rights, and offenders must be investigated
.