The Chromatin Remodeler BPTF Activates a Stemness Gene-Expression Program Essential for the Maintenance of Adult Hematopoietic Stem Cells

Xu, Bowen; Cai, Ling; Butler, Jason M.; Chen, Dongliang; Lu, Xiongdong; Allison, David F.; Lu, Rui; Rafii, Shahin; Parker, Joel S.; Zheng, Deyou; Wang, Gang Greg

doi:10.1016/j.stemcr.2018.01.020

Cited by 29 publications

(18 citation statements)

References 35 publications

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“…Its protein is a member of the TALE (three-amino acid loop extension) family homeodomain transcription factors [ 74 , 75 ] and well-known for its functions in lymphoblastic leukaemia [ 76 – 79 ] and several cancers [ 80 – 89 ]. PBX1 also plays roles in regulating developmental gene expression [ 90 ], maintaining stemness and self-renewal [ 80 , 91 , 92 ], and promoting the cell-cycle transition to the S phase [ 93 ]. Additionally, multiple lines of evidence obtained from in vivo and in vitro highlighted its functions as a pioneer factor [ 86 , 94 ].…”

Section: Resultsmentioning

confidence: 99%

Alternative splicing links histone modifications to stem cell fate decision

Zhao

Olson

et al. 2018

Genome Biol

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BackgroundUnderstanding the embryonic stem cell (ESC) fate decision between self-renewal and proper differentiation is important for developmental biology and regenerative medicine. Attention has focused on mechanisms involving histone modifications, alternative pre-messenger RNA splicing, and cell-cycle progression. However, their intricate interrelations and joint contributions to ESC fate decision remain unclear.ResultsWe analyze the transcriptomes and epigenomes of human ESC and five types of differentiated cells. We identify thousands of alternatively spliced exons and reveal their development and lineage-dependent characterizations. Several histone modifications show dynamic changes in alternatively spliced exons and three are strongly associated with 52.8% of alternative splicing events upon hESC differentiation. The histone modification-associated alternatively spliced genes predominantly function in G2/M phases and ATM/ATR-mediated DNA damage response pathway for cell differentiation, whereas other alternatively spliced genes are enriched in the G1 phase and pathways for self-renewal. These results imply a potential epigenetic mechanism by which some histone modifications contribute to ESC fate decision through the regulation of alternative splicing in specific pathways and cell-cycle genes. Supported by experimental validations and extended datasets from Roadmap/ENCODE projects, we exemplify this mechanism by a cell-cycle-related transcription factor, PBX1, which regulates the pluripotency regulatory network by binding to NANOG. We suggest that the isoform switch from PBX1a to PBX1b links H3K36me3 to hESC fate determination through the PSIP1/SRSF1 adaptor, which results in the exon skipping of PBX1.ConclusionWe reveal the mechanism by which alternative splicing links histone modifications to stem cell fate decision.Electronic supplementary materialThe online version of this article (10.1186/s13059-018-1512-3) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Alternative splicing links histone modifications to stem cell fate decision

Zhao

Olson

et al. 2018

Genome Biol

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“…Through its DDT domain (Fyodorov and Kadonaga, 2002), BPTF cooperates with ISWI to slide nucleosomes along DNA, changing access of promoter regions to transcription factors that drive gene transcription. In mammals, BPTF regulates cellular differentiation and homeostasis of specific cell-types and tissues, including the distal visceral endoderm (Landry et al, 2008), ecoplacental cone (Goller et al, 2008), hematopoietic stem/progenitor cells (Xu et al, 2018), mammary stem cells (Frey et al, 2017), T-cells (Wu et al, 2016), and melanocytes (Koludrovic et al, 2015). In Drosophila , the ortholog to BPTF, NURF301, regulates the heat shock response, pupation, spermatogenesis, and innate immunity (Badenhorst et al, 2002; Badenhorst et al, 2005; Kwon et al, 2008; Kwon et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Evolution of Yin and Yang isoforms of a chromatin remodeling subunit precedes the creation of two genes

Long

Zhao

et al. 2019

eLife

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Genes can encode multiple isoforms, broadening their functions and providing a molecular substrate to evolve phenotypic diversity. Evolution of isoform function is a potential route to adapt to new environments. Here we show that de novo, beneficial alleles in the nurf-1 gene became fixed in two laboratory lineages of C. elegans after isolation from the wild in 1951, before methods of cryopreservation were developed. nurf-1 encodes an ortholog of BPTF, a large (>300 kD) multidomain subunit of the NURF chromatin remodeling complex. Using CRISPR-Cas9 genome editing and transgenic rescue, we demonstrate that in C. elegans, nurf-1 has split into two, largely non-overlapping isoforms (NURF-1.D and NURF-1.B, which we call Yin and Yang, respectively) that share only two of 26 exons. Both isoforms are essential for normal gametogenesis but have opposite effects on male/female gamete differentiation. Reproduction in hermaphrodites, which involves production of both sperm and oocytes, requires a balance of these opposing Yin and Yang isoforms. Transgenic rescue and genetic position of the fixed mutations suggest that different isoforms are modified in each laboratory strain. In a related clade of Caenorhabditis nematodes, the shared exons have duplicated, resulting in the split of the Yin and Yang isoforms into separate genes, each containing approximately 200 amino acids of duplicated sequence that has undergone accelerated protein evolution following the duplication. Associated with this duplication event is the loss of two additional nurf-1 transcripts, including the long-form transcript and a newly identified, highly expressed transcript encoded by the duplicated exons. We propose these lost transcripts are non-functional side products necessary to transcribe the Yin and Yang transcripts in the same cells. Our work demonstrates how gene sharing, through the production of multiple isoforms, can precede the creation of new, independent genes.

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“…The loosened structure may facilitate the binding of various transcription factors to the regulatory motif, thereby activating the gene. [16][17][18] Chromatin remodeling is not an independent mechanism, but is regulated by multiple proteins, and is closely related to histone modifications. we thus further tested the binding between MLL, WDR5, and RBBP5 in the promoter region of HOXC8 and maximum nucleosome remodeling factor subunit PHD finger transcription factor (bromodomain and PHD finger transcription factor, BPTF) after siRNA-ASH2L interference.…”

Section: Discussionmentioning

confidence: 99%

<p>ASH2L-Promoted <em>HOXC8</em> Gene Expression Plays a Role in Mixed Lineage Leukemia-Rearranged Acute Leukemia</p>

Liu

et al. 2020

OTT

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Background: Mixed lineage leukemia (MLL) fusion protein alone exhibits poor histone lysine methyltransferase (HKMT) activity in catalyzing histone H3 Lys4 trimethylation (H3K4me3) in MLL-rearranged acute leukemia. Methods: To explore the HKMT effect of another regulatory protein within the complex of proteins associated with Set 1 (COMPASS), we analyzed the H3K4me3 modification of the HOXC8 promoter under the action of ASH2L regulation. Small interfering RNA of ASH2L, chromatin immunoprecipitation, real-time-PCR (RT-PCR), and Western blotting were used to detect the expression of specific regions of the HOXC8 promoter, RBBP5, WDR5, MLL, and BRTF in two MLL-rearranged acute leukemia cell lines (RS4:11 and THP-1 cells). Results: The gene and protein expression levels of HOXC8 were significantly downregulated upon treatment with ASH2L-siRNA (as analyzed by targeting specific regions of the HOXC8 promoter located 0 and 3 kb (-3.0 kb) upstream of the transcriptional start site in RSH:11 cells; and-3.0 and-2.0 kb upstream of the transcriptional start site, and +1.4 kb downstream of the transcriptional start site in THP-1 cells). The expression levels of the BRTF, RBBP5, WDR5, and MLL genes were significantly downregulated from the different transcriptional start sites of the HOXC8 promoter in the RSH:11 cell line (P < 0.05). Furthermore, the BPTF and RBBP5 genes were downregulated from the HOXC8 promoter in the THP-1 cell line (P < 0.05). Conclusion: Based on these results, we suggest a new concept of histone modification of the ASH2L protein in MLL-rearranged acute leukemia, which cannot carry out methyltransferase activity independently. The protein-protein interactions of ASH2L with other COMPASS members, such as MLL, WDR5, RBBP5, and chromatin remodeling factor BRTF, appear to be essential for its role in the activation of HOXC8 gene transcription.

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The Chromatin Remodeler BPTF Activates a Stemness Gene-Expression Program Essential for the Maintenance of Adult Hematopoietic Stem Cells

Cited by 29 publications

References 35 publications

Alternative splicing links histone modifications to stem cell fate decision

Alternative splicing links histone modifications to stem cell fate decision

Evolution of Yin and Yang isoforms of a chromatin remodeling subunit precedes the creation of two genes

<p>ASH2L-Promoted <em>HOXC8</em> Gene Expression Plays a Role in Mixed Lineage Leukemia-Rearranged Acute Leukemia</p>

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