Histone variant H3.3 maintains adult haematopoietic stem cell homeostasis by enforcing chromatin adaptability

Guo, Peipei; Liu, Ying; Geng, Fuqiang; Daman, Andrew W; Liu, Xiaoyu; Zhong, Liangwen; Ravishankar, Arjun; Lis, Raphaël; Durán, José Gabriel Barcia; Itkin, Tomer; Tang, Fanying; Zhang, Tuo; Xiang, Jenny; Shido, Koji; Ding, Bi-Sen; Wen, Desheng; Josefowicz, Steven Z.; Rafii, Shahin

doi:10.1038/s41556-021-00795-7

Cited by 26 publications

(20 citation statements)

References 68 publications

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“…Down-regulated genes have lost the activating mark H3K4me3 but gained the repressive mark H3K27me3 in dKO-N. Conversely, up-regulated genes have gained H3K4me3 but lost H3K27me3. We further found an expression increase in class II ERVs in dKO-N, consistent with H3.3-dependent repression of ERVs via H3K9me3 ( 65 , 66 ).…”

Section: Discussionsupporting

confidence: 83%

“…Downregulated genes have lost the activating mark H3K4me3 but gained the repressive mark H3K27me3 in dKO-N. Conversely, upregulated genes have gained H3K4me3 but lost H3K27me3. We further find an expression increase in class II ERVs in dKO-N, consistent with H3.3-dependent repression of ERVs via H3K9me3 (65,66). Together, our results convergently support the possibility that H3.3 establishes the neuronal transcriptome in large part by mediating establishment of the histone PTM landscape.…”

Section: Postmitotic H33 Mediates Developmental Acquisition Of Neuron...supporting

confidence: 84%

“…In embryonic and hematopoietic stem cells, H3.3 is required for silencing of endogenous retroviral elements (ERVs), in particular class I and II ERVs ( 65 , 66 ). Leveraging our transcriptome data, we assessed whether repetitive and transposable elements ( 67 ) became derepressed in dKO-N. Interestingly, we found one family of repetitive elements to be significantly up-regulated in dKO-N: the class II ERV IAPEY4_I-int LTR ERVK (FDR = 5.1E-6, FC = 1.86) ( SI Appendix , Fig.…”

Section: Resultsmentioning

confidence: 99%

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Postmitotic accumulation of histone variant H3.3 in new cortical neurons establishes neuronal chromatin, transcriptome, and identity

Funk

Qalieh

Doyle

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Histone variants, which can be expressed outside of S-phase and deposited DNA synthesis-independently, provide long-term histone replacement in postmitotic cells, including neurons. Beyond replenishment, histone variants also play active roles in gene regulation by modulating chromatin states or enabling nucleosome turnover. Here, we uncover crucial roles for the histone H3 variant H3.3 in neuronal development. We find that newborn cortical excitatory neurons, which have only just completed replication-coupled deposition of canonical H3.1 and H3.2, substantially accumulate H3.3 immediately postmitosis. Codeletion of H3.3-encoding genes H3f3a and H3f3b from newly postmitotic neurons abrogates H3.3 accumulation, markedly alters the histone posttranslational modification landscape, and causes widespread disruptions to the establishment of the neuronal transcriptome. These changes coincide with developmental phenotypes in neuronal identities and axon projections. Thus, preexisting, replication-dependent histones are insufficient for establishing neuronal chromatin and transcriptome; de novo H3.3 is required. Stage-dependent deletion of H3f3a and H3f3b from 1) cycling neural progenitor cells, 2) neurons immediately postmitosis, or 3) several days later, reveals the first postmitotic days to be a critical window for de novo H3.3. After H3.3 accumulation within this developmental window, codeletion of H3f3a and H3f3b does not lead to immediate H3.3 loss, but causes progressive H3.3 depletion over several months without widespread transcriptional disruptions or cellular phenotypes. Our study thus uncovers key developmental roles for de novo H3.3 in establishing neuronal chromatin, transcriptome, identity, and connectivity immediately postmitosis that are distinct from its role in maintaining total histone H3 levels over the neuronal lifespan.

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Section: Discussionsupporting

confidence: 83%

Section: Postmitotic H33 Mediates Developmental Acquisition Of Neuron...supporting

confidence: 84%

Section: Resultsmentioning

confidence: 99%

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Postmitotic accumulation of histone variant H3.3 in new cortical neurons establishes neuronal chromatin, transcriptome, and identity

Funk

Qalieh

Doyle

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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“…We further detected 16 ZNF genes that exhibit a co-expression pattern with the histone genes in the specific stem cell and growth conditions (Figure 6B and C ), of which seven genes were closely located within chromosome 19 (13q42-13q43) (Figure 6D ). Previous studies reported the connection between stem cell identity and histones or zinc fingers: the activation of multiple histone variants, including H1, H2A and H3, in maintaining ESC pluripotency and ESC fate ( 103 , 104 ), the role of histone variant H3.3 on the maintenance of HSC stemness ( 105 ), and co-localized 31 zinc-finger genes within topologically associating domains on chr19 in human ESCs ( 106 ). We found a higher co-expression pattern between histones and co-localized zinc fingers in ESCs in xenogenic medium and HSCs in L-GLN medium (Figure 6A and C ).…”

Section: Discussionmentioning

confidence: 99%

Comprehensive comparison of gene expression diversity among a variety of human stem cells

Yamatani

Nakai

2022

NAR Genomics and Bioinformatics

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Several factors, including tissue origins and culture conditions, affect the gene expression of undifferentiated stem cells. However, understanding the basic identity across different stem cells has not been pursued well despite its importance in stem cell biology. Thus, we aimed to rank the relative importance of multiple factors to gene expression profile among undifferentiated human stem cells by analyzing publicly available RNA-seq datasets. We first conducted batch effect correction to avoid undefined variance in the dataset as possible. Then, we highlighted the relative impact of biological and technical factors among undifferentiated stem cell types: a more influence on tissue origins in induced pluripotent stem cells than in other stem cell types; a stronger impact of culture condition in embryonic stem cells and somatic stem cell types, including mesenchymal stem cells and hematopoietic stem cells. In addition, we found that a characteristic gene module, enriched in histones, exhibits higher expression across different stem cell types that were annotated by specific culture conditions. This tendency was also observed in mouse stem cell RNA-seq data. Our findings would help to obtain general insights into stem cell quality, such as the balance of differentiation potentials that undifferentiated stem cells possess.

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“…KDM6A/6B is correspondent H3K27me3 “eraser,” reducing its methylation level. H3K27me3 is considered a transcriptional repressive marker and could inhibit target gene expression by condensing chromatin ( 27 ). We first examined the mRNA level of KDM6A/6B and found that only KDM6A was upregulated by PA stimulation ( Figure 2A ).…”

Section: Resultsmentioning

confidence: 99%

GSK-J4, a Specific Histone Lysine Demethylase 6A Inhibitor, Ameliorates Lipotoxicity to Cardiomyocytes via Preserving H3K27 Methylation and Reducing Ferroptosis

Liu

Wen

et al. 2022

Front. Cardiovasc. Med.

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Changes in modern lifestyle provoke a series of metabolic stresses such as hyperlipidemia. Excessive free fatty acids induce cardiomyocyte metabolic reprogramming and rearrangement of the lipid content of cardiomyocyte and promote oxidative stress. As a newly defined lipid peroxidation-related cell death pathway, the role of ferroptosis in metabolic stress-induced cardiomyocyte injury is poorly revealed. Our work indicates that GSK-J4, a histone lysine demethylase 6A/6B dual inhibitor, can alleviate palmitic acid (PA)-induced hypersensitivity to ferroptosis by suppressing H3K27 demethylation. Mechanistically, PA stimulation reduces the H3K27me3 level and hence promotes the expression of ACSL4, a key lipid modulator of ferroptosis. GSK-J4 pretreatment significantly preserves the H3K27me3 level and reduces the ACSL4 level. GSK-J4 also reduces reactive oxygen species to alleviate oxidative stress, which further decreases lipid peroxidation. Taken together, our data suggest that cardiomyocyte undergoes epigenetic reprogramming under metabolic challenges, rearranging lipid content, and sensitizing to ferroptosis. GSK-J4 can be a potential drug for treating hyperlipidemia-induced cardiomyocyte injury by targeting epigenetic modulations.

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Histone variant H3.3 maintains adult haematopoietic stem cell homeostasis by enforcing chromatin adaptability

Cited by 26 publications

References 68 publications

Postmitotic accumulation of histone variant H3.3 in new cortical neurons establishes neuronal chromatin, transcriptome, and identity

Postmitotic accumulation of histone variant H3.3 in new cortical neurons establishes neuronal chromatin, transcriptome, and identity

Comprehensive comparison of gene expression diversity among a variety of human stem cells

GSK-J4, a Specific Histone Lysine Demethylase 6A Inhibitor, Ameliorates Lipotoxicity to Cardiomyocytes via Preserving H3K27 Methylation and Reducing Ferroptosis

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