Dataset Information

Setd2 deficiency impairs hematopoietic stem cell self-renewal and causes malignant transformation.

ABSTRACT: The histone H3 lysine 36 methyltransferase SETD2 is frequently mutated in various cancers, including leukemia. However, there has not been any functional model to show the contribution of SETD2 in hematopoiesis or the causal role of SETD2 mutation in tumorigenesis. In this study, using a conditional Setd2 knockout mouse model, we show that Setd2 deficiency skews hematopoietic differentiation and reduces the number of multipotent progenitors; although the number of phenotypic hematopoietic stem cells (HSCs) in Setd2-deleted mice is unchanged, functional assays, including serial BM transplantation, reveal that the self-renewal and competitiveness of HSCs are impaired. Intriguingly, Setd2-deleted HSCs, through a latency period, can acquire abilities to overcome the growth disadvantage and eventually give rise to hematopoietic malignancy characteristic of myelodysplastic syndrome. Gene expression profile of Setd2-deleted hematopoietic stem/progenitor cells (HSPCs) partially resembles that of Dnmt3a/Tet2 double knockout HSPCs, showing activation of the erythroid transcription factor Klf1-related pathway, which plays an important role in hematopoietic malignant transformation. Setd2 deficiency also induces DNA replication stress in HSCs, as reflected by an activated E2F gene regulatory network and repressed expression of the ribonucleotide reductase subunit Rrm2b, which results in proliferation and cell cycle abnormalities and genomic instability, allowing accumulation of secondary mutation(s) that synergistically contributes to tumorigenesis. Thus, our results demonstrate that Setd2 is required for HSC self-renewal, and provide evidence supporting the causal role of Setd2 deficiency in tumorigenesis. The underlying mechanism shall advance our understanding of epigenetic regulation of cancer and provide potential new therapeutic targets.

SUBMITTER: Zhang YL

PROVIDER: S-EPMC5939047 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Setd2 deficiency impairs hematopoietic stem cell self-renewal and causes malignant transformation.

Zhang Yuan-Liang YL Sun Jie-Wen JW Xie Yin-Yin YY Zhou Yan Y Liu Ping P Song Jia-Chun JC Xu Chun-Hui CH Wang Lan L Liu Dan D Xu Ai-Ning AN Chen Zhu Z Chen Sai-Juan SJ Sun Xiao-Jian XJ Huang Qiu-Hua QH

Cell research 20180312 4

The histone H3 lysine 36 methyltransferase SETD2 is frequently mutated in various cancers, including leukemia. However, there has not been any functional model to show the contribution of SETD2 in hematopoiesis or the causal role of SETD2 mutation in tumorigenesis. In this study, using a conditional Setd2 knockout mouse model, we show that Setd2 deficiency skews hematopoietic differentiation and reduces the number of multipotent progenitors; although the number of phenotypic hematopoietic stem c ...[more]

PMID: 29531312

Similar Datasets

Project description:Purpose: The histone H3 lysine 36 methyltransferase SETD2 is frequently mutated in various cancers, including leukemia. However, there has not been any functional model to show the contribution of SETD2 in hematopoiesis or the causal role of SETD2 mutation in tumorigenesis. In this study, using a conditional Setd2 knock-out (KO) mouse model, we show that Setd2 deficiency skews hematopoietic differentiation and impaired HSC (hematopoietic stem cell) self-renewal. Intriguingly, Setd2-deleted HSCs, through a latency period, can acquire abilities to overcome the growth disadvantage and eventually develop into hematopoietic malignancy characteristic of myelodysplastic syndrome (MDS). This study aimed at finding the mechanism controlled by Setd2, which was required for MDS formation. Methods: Young and old Setd2 WT and KO LSKs (Lin-c-Kit+Sca1+) were generated by deep RNA-seq, using Illumina Hiseq2500. Using Stringtie (version:1.3.0) software to analyze the sequence reads that passed quality filter to acquire the expression level of all genes. qRT–PCR validation was performed using SYBR Green assays. Young Setd2 WT and KO LSKs were also generated by whole genome bisulfite sequencing (WGBS), using Illumina Hiseq2500. Results: Using an optimized data analysis workflow, 246 genes down-regulated and 226 up-regulated, showed significant differential expression (fold change, FC ≤ 0.5 or FC ≥ 2; p < 0.05) between young WT and KO LSKs. Old LSKs displayed about 1112 down-regulated and 777 up-regulated genes between WT and KO. The results of WGBS showed that the Setd2 KO genome carries a much larger number of hypomethylated DMRs (different methylation regions) relative to hypermethylated ones (5,839 versus 1,294). Conclusions: Through RNA-seq, gene expression profile of young Setd2-deleted LSKs partially resembles the Dnmt3a/Tet2 double knock-out. WGBS also indicated that Setd2 deficiency can regulate the distribution of whole genome DNA methylation. Furthermore, young Setd2 deficiency also induces DNA replication stress in HSCs, as reflected by activated E2F gene regulatory network and repressed ribonucleotide reductase subunit Rrm2b. Old Setd2-deleted LSKs displayed a MDS related transcriptional signature.

Dataset Information

Setd2 deficiency impairs hematopoietic stem cell self-renewal and causes malignant transformation.

Publications

Setd2 deficiency impairs hematopoietic stem cell self-renewal and causes malignant transformation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets