Uhrf1 governs the proliferation and differentiation of muscle satellite cells

Sakai, Hiroshi; Sawada, Yuichiro; Tokunaga, Naohito; Tanaka, Kaori; Nakagawa, So; Sakakibara, Iori; Ono, Yusuke; Fukada, So‐ichiro; Ohkawa, Yasuyuki; Kikugawa, Tadahiko; Sakaguchi, Takashi; Imai, Yuuki

doi:10.1016/j.isci.2022.103928

Cited by 6 publications

(5 citation statements)

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“…This agrees with a previous report that UHRF1 binds gene promoters and mediates silencing of the associated genes in cancer cells (Mancini et al, 2021). Moreover, we observed that UHRF1-TTD is enriched in enhancers with a strong connection to genes of cell-type-specific processes and celltype-specific TFs in hepatic cells, in line with reports of UHRF1 involvement in cell-type-specific gene regulation during lineage specification (Kim et al, 2018;Obata et al, 2014;Ramesh et al, 2016;Sakai et al, 2022;Yamashita et al, 2018). Conversely, the enhancers of genes downregulated by full-length hUHRF1 in a TTDdependent manner in HCT116 cells demonstrate an enrichment in H3K4me1-K9me2, indicating that UHRF1 contributes to silencing of genes with H3K4me1-K9me2 marked enhancers.…”

Section: Discussionsupporting

confidence: 93%

“…Taken together, our data clearly support a role for UHRF1 in differentiation and regulation of cell-type-specific processes, mediated by TTD targeting. Our finding that H3K4me1-K9me2 and UHRF1-TTD flank the targets of cell-type-specific TFs in HepG2 cells provides physiological context for this histone double mark, and a potential read/write mechanism via TFs and TTD, while providing an explanation for the previously reported role of UHRF1 in cellular differentiation (Kim et al, 2018;Obata et al, 2014;Ramesh et al, 2016;Sakai et al, 2022;Yamashita et al, 2018).…”

Section: Uhrf1-ttd and H3k4me1-k9me2 Flank Targets Of Cell-type-speci...supporting

confidence: 55%

“…In cancer cells, UHRF1 is often upregulated, and it can bind gene promoters to mediate silencing of the associated genes (Mancini et al, 2021 ). Generally, UHRF1 disruption results in strong DNA hypomethylation and reduced cell‐type‐specific gene expression, pointing towards its important role as a regulator of cell lineage specification during differentiation (Kim et al, 2018 ; Obata et al, 2014 ; Ramesh et al, 2016 ; Sakai et al, 2022 ; Yamashita et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

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Refined read‐out: The hUHRF1 Tandem‐Tudor domain prefers binding to histone H3 tails containing K4me1 in the context of H3K9me2/3

Choudalakis,

Kungulovski,

Mauser

et al. 2023

Protein Science

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UHRF1 is an essential chromatin protein required for DNA methylation maintenance, mammalian development and gene regulation. We investigated the Tandem‐Tudor domain (TTD) of human UHRF1 that is known to bind H3K9me2/3 histones and is a major driver of UHRF1 localization in cells. We verified binding to H3K9me2/3 but unexpectedly discovered stronger binding to H3 peptides and mononucleosomes containing K9me2/3 with additional K4me1. We investigated the combined binding of TTD to H3K4me1‐K9me2/3 vs. H3K9me2/3, engineered mutants with specific and differential changes of binding, and discovered a novel read‐out mechanism for H3K4me1 in an H3K9me2/3 context that is based on the interaction of R207 with the H3K4me1 methyl group and on counting the H‐bond capacity of H3K4. Individual TTD mutants showed up to 10,000‐fold preference for the double modified peptides, suggesting that after a conformational change, WT TTD could exhibit similar effects. The frequent appearance of H3K4me1‐K9me2 regions demonstrated in our TTD pulldown and ChIP‐western blot data suggests that it has specific biological roles. Chromatin pull‐down of TTD from HepG2 cells and ChIP‐seq data of full‐length murine UHRF1 correlate with H3K4me1 profiles indicating that the H3K4me1‐K9me2/3 interaction of TTD influences chromatin binding of full‐length UHRF1. We demonstrated the H3K4me1‐K9me2/3 specific binding of UHRF1‐TTD to enhancers and promoters of cell‐type specific genes, at the flanks of cell‐type specific transcription factor binding sites, and provided evidence supporting an H3K4me1‐K9me2/3 dependent and TTD mediated down‐regulation of these genes by UHRF1, illustrating the physiological function of UHRF1‐TTD binding to H3K4me1‐K9me2/3 double marks in a cellular context.This article is protected by copyright. All rights reserved.

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Section: Discussionsupporting

confidence: 93%

Section: Uhrf1-ttd and H3k4me1-k9me2 Flank Targets Of Cell-type-speci...supporting

confidence: 55%

Section: Introductionmentioning

confidence: 99%

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Refined read‐out: The hUHRF1 Tandem‐Tudor domain prefers binding to histone H3 tails containing K4me1 in the context of H3K9me2/3

Choudalakis,

Kungulovski,

Mauser

et al. 2023

Protein Science

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“…These phenotypes of low bone and high fat mass were also observed in Aro Δ aP2 mice at the age of 24 weeks (Figure S3 A-E). It has been reported that some Cre mouse lines develop skeletal dysplasia or abnormal regeneration in tissues (Rodda & McMahon, 2006; Sakai et al, 2022). Therefore, we tested whether these phenotypes of Aro Δ aP2 mice were due to the influence of the Cre mouse line.…”

Section: Resultsmentioning

confidence: 99%

Aromatase in adipose tissue exerts an osteoprotective function in male mice via phosphate regulation

Ikedo,

Yamashita,

Hoshino

et al. 2024

Preprint

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Aromatase contributes to maintenance of bone mass because male patients with loss-of-function mutations ofCYP19A1exhibit bone loss. Treatment with aromatase inhibitor also causes bone loss in men and post-menopausal women, suggesting that part of the anabolic effect of testosterone in men is dependent on estradiol (E2) biosynthesized by aromatase in non-gonadal tissues. It remains unclear how locally biosynthesized E2 contributes to maintenance of bone mass. We examined the function of aromatase in local tissues rather than gonads using cell-type specific aromatase knockout (KO) mice. Because osteoblast-specific aromatase KO mice exhibited no bone phenotype, we focused on adipose tissue, known as a reservoir of steroid hormones and analyzed the bone phenotypes of adipose tissue-specific aromatase KO mice (AroΔaP2). Sixteen-week-old maleAroΔaP2mice exhibited significantly lower bone mineral density in tibia and femur, especially in trabecular bone, than controls. Bone histomorphometry showed thatAroΔaP2mice exhibited an insufficient calcification bone phenotype with increased osteoid volume and width, and decreased osteoclast area and numbers. Moreover, serum phosphate, renal phosphate reabsorption and FGF23 were significantly lower inAroΔaP2, suggesting that the insufficient calcification phenotype inAroΔaP2was not caused by excessive FGF23 activities. Finally, we analyzed NaPi2a and NaPi2c, phosphate transporters localized in the kidney, and found that protein levels in renal brush border membrane vesicles were lower inAroΔaP2. These results indicate that estrogens locally biosynthesized by aromatase in adipocytes can play a significant role in bone mass maintenance via regulation of phosphate reabsorption in the kidney by NaPi2.Impact StatementMale adipocyte-specific aromatase KO mice (AroΔaP2) exhibited bone loss and increased osteoid due to decreased serum phosphate and urinary phosphate reabsorption as a result of reduced NaPi2 proteins expression in the kidney.

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“…In cancer cells, UHRF1 is often upregulated, and it can bind gene promoters to mediate silencing of the associated genes (Mancini et al, 2021). Generally, UHRF1 disruption results in strong DNA hypomethylation and reduced celltype-specific gene expression, pointing towards its important role as a regulator of cell lineage specification during differentiation (Kim et al, 2018;Obata et al, 2014;Ramesh et al, 2016;Sakai et al, 2022;Yamashita et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Refined read-out: The hUHRF1 Tandem-Tudor domain prefers binding to histone H3 tails containing K4me1 in the context of H3K9me2/3

Choudalakis,

Kungulovski,

Mauser

et al. 2023

Preprint

View full text Add to dashboard Cite

UHRF1 is an essential chromatin protein required for DNA methylation maintenance, mammalian development and gene regulation. We investigated the Tandem-Tudor domain (TTD) of human UHRF1 that is known to bind H3K9me2/3 histones and is a major driver of UHRF1 localization in cells. We verified binding to H3K9me2/3 but unexpectedly discovered stronger binding to H3 peptides and mononucleosomes containing K9me2/3 with additional K4me1. We investigated the combined binding of TTD to H3K4me1-K9me2/3 vs. H3K9me2/3, engineered mutants with specific and differential changes of binding, and discovered a novel read-out mechanism for H3K4me1 in an H3K9me2/3 context that is based on the interaction of R207 with the H3K4me1 methyl group and on counting the H-bond capacity of H3K4. Individual TTD mutants showed up to 10,000-fold preference for the double modified peptides, suggesting that after a conformational change, WT TTD could exhibit similar effects. The frequent appearance of H3K4me1-K9me2 regions demonstrated in our TTD pulldown and ChIP-western blot data suggests that it has specific biological roles. Chromatin pull-down of TTD from HepG2 cells and ChIP-seq data of full-length murine UHRF1 correlate with H3K4me1 profiles indicating that the H3K4me1-K9me2/3 interaction of TTD influences chromatin binding of full-length UHRF1. We demonstrated the H3K4me1-K9me2/3 specific binding of UHRF1-TTD to enhancers and promoters of cell-type specific genes, at the flanks of cell-type specific transcription factor binding sites, and provided evidence supporting an H3K4me1-K9me2/3 dependent and TTD mediated down-regulation of these genes by UHRF1, illustrating the physiological function of UHRF1-TTD binding to H3K4me1-K9me2/3 double marks in a cellular context.

show abstract

Uhrf1 governs the proliferation and differentiation of muscle satellite cells

Cited by 6 publications

References 48 publications

Refined read‐out: The hUHRF1 Tandem‐Tudor domain prefers binding to histone H3 tails containing K4me1 in the context of H3K9me2/3

Refined read‐out: The hUHRF1 Tandem‐Tudor domain prefers binding to histone H3 tails containing K4me1 in the context of H3K9me2/3

Aromatase in adipose tissue exerts an osteoprotective function in male mice via phosphate regulation

Refined read-out: The hUHRF1 Tandem-Tudor domain prefers binding to histone H3 tails containing K4me1 in the context of H3K9me2/3

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