Histone H2B monoubiquitination is a critical epigenetic switch for the regulation of autophagy

Chen, Su; Jing, Yuanya; Kang, Xuan; Lu, Yang; Wang, Da-Liang; Zhang, Wei; Zhang, Lei; Chen, Ping; Chang, Jian-Feng; Yang, Xiaomei; Sun, Fang-Lin

doi:10.1093/nar/gkw1025

Cited by 35 publications

(38 citation statements)

References 67 publications

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“…RT-PCR assay was performed according to our previous reports [30,35,44]. Briefly, cells were lysed to isolate total RNA using TRIzol reagent (Invitrogen, #15596-026) according to the manufacturer's instructions.…”

Section: Rt-pcr Assaymentioning

confidence: 99%

“…An increasing number of studies have indicated that H2Bub1 plays significant roles in various biological processes. H2Bub1 levels are strikingly decreased during starvation-induced autophagy, and loss of H2Bub1 results in autophagosome formation and the activation of autophagy [35,36]. Levels of H2Bub1 are increased significantly during ESC differentiation, and this upregulation of H2Bub1 is required for efficient ESC differentiation.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, our group recently suggested that H2Bub1 is also a critical epigenetic marker for the regulation of autophagy. H2Bub1 levels are strikingly decreased during starvation-induced autophagy, and loss of H2Bub1 results in autophagosome formation and the activation of autophagy [35,36].…”

Section: Introductionmentioning

confidence: 99%

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Epigenetic regulation of ferroptosis by H2B monoubiquitination and p53

Wang

Zhang³

et al. 2019

EMBO Reports

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159

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Monoubiquitination of histone H2B on lysine 120 (H2Bub1) is an epigenetic mark generally associated with transcriptional activation, yet the global functions of H2Bub1 remain poorly understood. Ferroptosis is a form of non‐apoptotic cell death characterized by the iron‐dependent overproduction of lipid hydroperoxides, which can be inhibited by the antioxidant activity of the solute carrier family member 11 (SLC7A11/xCT), a component of the cystine/glutamate antiporter. Whether nuclear events participate in the regulation of ferroptosis is largely unknown. Here, we show that the levels of H2Bub1 are decreased during erastin‐induced ferroptosis and that loss of H2Bub1 increases the cellular sensitivity to ferroptosis. H2Bub1 epigenetically activates the expression of SLC7A11. Additionally, we show that the tumor suppressor p53 negatively regulates H2Bub1 levels independently of p53's transcription factor activity by promoting the nuclear translocation of the deubiquitinase USP7. Moreover, our studies reveal that p53 decreases H2Bub1 occupancy on the SLC7A11 gene regulatory region and represses the expression of SLC7A11 during erastin treatment. These data not only suggest a noncanonical role of p53 in chromatin regulation but also link p53 to ferroptosis via an H2Bub1‐mediated epigenetic pathway. Overall, our work uncovers a previously unappreciated epigenetic mechanism for the regulation of ferroptosis.

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Section: Rt-pcr Assaymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Epigenetic regulation of ferroptosis by H2B monoubiquitination and p53

Wang

Zhang³

et al. 2019

EMBO Reports

Self Cite

159

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“…Mechanisms contributing to abnormal protein clearance, such as autophagy and proteosomal degradation, are very high in ESC. For instance, it was observed that deubiquitination of EPG5, a protein mediating autophagosome/lysosome fusion, by USP8 reinforces EPG5 function and enhances autophagy activity in ESCs . Surprinsingly, low levels of H2Bub in ESC, maintained by USP44, also contribute to high levels of autophagy and to the proper regulation of the levels of pluripotency factors in ESC …”

Section: Ubiquitination Contributes To High Levels Of Autophagy and Pmentioning

confidence: 99%

Ubiquitin Dynamics in Stem Cell Biology: Current Challenges and Perspectives

Dieuleveult

Miotto

2020

BioEssays

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Ubiquitination plays a central role in the regulation of stem cell self‐renewal, propagation, and differentiation. In this review, the functions of ubiquitin dynamics in a myriad of cellular processes, acting along side the pluripotency network, to regulate embryonic stem cell identity are highlighted. The implication of deubiquitinases (DUBs) and E3 Ubiquitin (Ub) ligases in cellular functions beyond protein degradation is reported, including key functions in the regulation of mRNA stability, protein translation, and intra‐cellular trafficking; and how it affects cell metabolism, the micro‐environment, and chromatin organization is discussed. Finally, unsolved issues in the field are emphasized and will need to be tackled in order to fully understand the contribution of ubiquitin dynamics to stem cell self‐renewal and differentiation.

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“…EHMT2/G9a (euchromatic histone lysine methyltransferase 2) [14] and EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit) [15] have both been implicated in autophagy repression under serum starvation by increasing H3K9me2 and H3K27me3 histone mark levels, respectively, of certain autophagy-associated genes. Furthermore, autophagy induction has been demonstrated to affect total H3R17me2, H4K16ac, and H2BK120ub levels through CARM1 (coactivator associated arginine methyltransferase 1) [16], KAT8/hMOF (lysine acetyltransferase 8) [17], and the deubiquitinase USP44 (ubiquitin specific peptidase 44) [18], respectively. These alterations affect transcription of genes involved in (the regulation of) autophagy and therefore function as an epigenetic switch in autophagy regulation under various starvation conditions and upon MTOR (mechanistic target of rapamycin kinase) inhibition.…”

Section: Introductionmentioning

confidence: 99%

Transcriptional and epigenetic profiling of nutrient-deprived cells to identify novel regulators of autophagy

et al. 2018

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Macroautophagy (hereafter autophagy) is a lysosomal degradation pathway critical for maintaining cellular homeostasis and viability, and is predominantly regarded as a rapid and dynamic cytoplasmic process. To increase our understanding of the transcriptional and epigenetic events associated with autophagy, we performed extensive genome-wide transcriptomic and epigenomic profiling after nutrient deprivation in human autophagy-proficient and autophagy-deficient cells. We observed that nutrient deprivation leads to the transcriptional induction of numerous autophagy-associated genes. These transcriptional changes are reflected at the epigenetic level (H3K4me3, H3K27ac, and H3K56ac) and are independent of autophagic flux. As a proof of principle that this resource can be used to identify novel autophagy regulators, we followed up on one identified target: EGR1 (early growth response 1), which indeed appears to be a central transcriptional regulator of autophagy by affecting autophagy-associated gene expression and autophagic flux. Taken together, these data stress the relevance of transcriptional and epigenetic regulation of autophagy and can be used as a resource to identify (novel) factors involved in autophagy regulation.

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Histone H2B monoubiquitination is a critical epigenetic switch for the regulation of autophagy

Cited by 35 publications

References 67 publications

Epigenetic regulation of ferroptosis by H2B monoubiquitination and p53

Epigenetic regulation of ferroptosis by H2B monoubiquitination and p53

Ubiquitin Dynamics in Stem Cell Biology: Current Challenges and Perspectives

Transcriptional and epigenetic profiling of nutrient-deprived cells to identify novel regulators of autophagy

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