UHRF1 is required for basal stem cell proliferation in response to airway injury

Xiang, Handan; Yuan, Lifeng; Gao, Xia; Alexander, Peter; Lopez, Omar; Lau, Calvin E.; Ding, Yi; Chong, Mengyang; Sun, Tao; Chen, Rui; Liu, Si Qi; Wu, Haiyang; Wan, Ying; Randell, Scott H.; Li, Qi Jing; Wang, Xiao Fan

doi:10.1038/celldisc.2017.19

Cited by 30 publications

(25 citation statements)

References 40 publications

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“…One mechanism through which various states of DNA methylation can affect proliferation is by transcription. Consistently, UHRF1 can in this way regulate cell cycle progression via effects on expression of pRB and G1 phase cell cycle inhibitory protein expression in cultured COS-7 and HeLa cells [31], via effects on p21 in T cells [26] and in bronchial epithelial stem-like cells at least partially through the p15 pathway [24]. Analysis of the transcriptome of normal and Uhrf1-deficient NSCs revealed significant changes in the transcriptome.…”

Section: Discussionmentioning

confidence: 74%

“…UHRF1 is expressed in highly proliferating cells including cancer cell lines, NSCs in the embryonic brain, and bronchial epithelial stem-like cells and is downregulated during cell differentiation or quiescence [18][19][20][21][22][23][24]. Depletion of UHRF1 abrogates proliferation in many different cell lines as well as in epithelial and immune cells in vivo [18,[24][25][26][27][28]. However, conditional deletion of Uhrf1 in the embryonic cortex has minor effects on proliferation and instead causes a delayed neurodegeneration phenotype [22].…”

Section: Introductionmentioning

confidence: 99%

“…In cell types where it controls proliferation, it has been shown to be essential for S-phase entry [18] and consistently, overexpression can force S-phase entry even in terminally differentiated myotubes in vitro [18,29]. UHRF1 can repress factors that serve to restrain S-phase entry in cell lines, such as the S-phase cell cycle entry regulator pRB [30] and the cell cycle regulator cyclin-dependent kinase inhibitor 1A (p21 Cip1 or p21) which blocks cyclinD/CDK2,4 activation of pRB via its hyperphosphorylation [24,26,31]. Here, we show that conditional deletion of UHRF1 in neural progenitor cells leads to Cdkn1a derepression, failure of S-phase entry and as a consequence a marked decrease of self-renewal with a concomitant loss of newly born neurons in the adult brain.…”

Section: Introductionmentioning

confidence: 99%

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UHRF1 Licensed Self-Renewal of Active Adult Neural Stem Cells

et al. 2018

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Adult neurogenesis in the brain continuously seeds new neurons throughout life, but how homeostasis of adult neural stem cells (NSCs) is maintained is incompletely understood. Here, we demonstrate that the DNA methylation adapter ubiquitin-like, containing PHD and RING finger domains-1 (UHRF1) is expressed in, and regulates proliferation of, the active but not quiescent pool of adult neural progenitor cells. Mice with a neural stem cell-specific deficiency in UHRF1 exhibit a massive depletion of neurogenesis resulting in a collapse of formation of new neurons. In the absence of UHRF1, NSCs unexpectedly remain in the cell cycle but with a 17-fold increased cell cycle length due to a failure of replication phase entry caused by promoter demethylation and derepression of Cdkn1a, which encodes the cyclin-dependent kinase inhibitor p21. UHRF1 does not affect the proportion progenitor cells active within the cell cycle but among these cells, UHRF1 is critical for licensing replication re-entry. Therefore, this study shows that a UHRF1-Cdkn1a axis is essential for the control of stem cell self-renewal and neurogenesis in the adult brain. Stem Cells 2018;36:1736-1751.

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Section: Discussionmentioning

confidence: 74%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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UHRF1 Licensed Self-Renewal of Active Adult Neural Stem Cells

et al. 2018

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“…UHRF1 associates with the DNA methyltransferase DNMT1 and is required for DNA methylation (26). UHRF1 has also been implicated in replisome assembly (57,58) and its phosphorylation oscillates during the cell cycle (59).…”

Section: Resultsmentioning

confidence: 99%

In silicoAPC/C substrate discovery reveals cell cycle degradation of chromatin regulators including UHRF1

Kernan

Martinez-Chacin

Wang

et al. 2020

Preprint

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The Anaphase-Promoting Complex/Cyclosome (APC/C) is an E3 ubiquitin ligase and critical regulator of cell cycle progression. Despite its vital role, it has remained challenging to globally map APC/C substrates. By combining orthogonal features of known substrates, we predicted APC/C substrates in silico. This analysis identified many known substrates and suggested numerous candidates. Unexpectedly, chromatin regulatory proteins are enriched among putative substrates and we show that several chromatin proteins bind APC/C, oscillate during the cell cycle and are degraded following APC/C activation, consistent with being direct APC/C substrates. Additional analysis revealed detailed mechanisms of ubiquitylation for UHRF1, a key chromatin regulator involved in histone ubiquitylation and DNA methylation maintenance. Disrupting UHRF1 degradation at mitotic exit accelerates G1-phase cell cycle progression and perturbs global DNA methylation patterning in the genome. We conclude that APC/C coordinates crosstalk between cell cycle and chromatin regulatory proteins. This has potential consequences in normal cell physiology, where the chromatin environment changes depending on proliferative state, as well as in disease.

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“…The expression of PCNA protein may be used as an indicator of cell proliferation ( 17 ), and thus was used to assess the proliferation of PASMCs by immunohistochemical staining. The expression of PCNA protein was identified in the nucleus of PASMCs in both the HPH and control groups ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Effects of FHL1 and P21 on hypoxia‑induced pulmonary vascular remodeling in neonatal rats

Yao

et al. 2017

Exp Ther Med

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Numerous studies have demonstrated that altered expression levels of four and a half LIM domains 1 (FHL1) and P21 are necessary for hypoxia-induced pulmonary vascular remodeling in both adult rats and human patients with idiopathic pulmonary arterial hypertension. However, whether FHL1 and P21 are present in the pulmonary artery and whether these proteins affect pulmonary vascular remodeling in hypoxia-induced pulmonary hypertension (HPH) in neonatal rats remain unknown. The present study investigated the effects of altered FHL1 and P21 expression on pulmonary vascular remodeling in neonatal rats with HPH. A total of 32 newborn Sprague-Dawley rats were exposed to hypoxia or room air for 7 or 14 days (n=8/subgroup). Parameters including the percentage of medial wall thickness (WT%), the percentage of medial wall area (WA%), right ventricular (RV) mean pressure, RV hypertrophy index (RVHI) and RV systolic pressure (RVSP) were measured to evaluate the development of HPH. Additionally, the expressions of FHL1 and P21 in the pulmonary artery smooth muscle cells (PASMCs) were measured by reverse transcription-quantitative polymerase chain reaction, western blot analysis and immunohistochemical staining. WA%, WT%, RV mean pressure, RVHI and RVSP were significantly increased in the HPH model group when compared with the control group (P<0.01). The protein expression levels of FHL1 were significantly increased in the HPH group (P<0.05), while the mRNA and protein expression levels of P21 were significantly reduced (P<0.05). Pearson correlation analysis indicated that the protein expressions of FHL1 and P21 were correlated with WA% and WT% (all P<0.001), and that the protein expression of P21 was negatively correlated with that of FHL1 (P<0.01). The results indicated that the expressions of FHL1 and P21 were altered in the PASMCs of newborn rats with HPH. Furthermore, FHL1 and P21 may serve important roles in pulmonary vascular remodeling.

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UHRF1 is required for basal stem cell proliferation in response to airway injury

Cited by 30 publications

References 40 publications

UHRF1 Licensed Self-Renewal of Active Adult Neural Stem Cells

UHRF1 Licensed Self-Renewal of Active Adult Neural Stem Cells

In silicoAPC/C substrate discovery reveals cell cycle degradation of chromatin regulators including UHRF1

Effects of FHL1 and P21 on hypoxia‑induced pulmonary vascular remodeling in neonatal rats

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