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HIRA is expressed in the embryonic cerebral cortex and NPCs. (A) Western blot analysis of the protein levels of HIRA, PAX6, and TUJ1 in the mouse cerebral cortex during embryonic development. β-Actin was used as a control. (B–D) The bar graph displays the relative band intensity of HIRA (B), PAX6 (C), and TUJ1 (D) from embryonic day 13 to 18 (E13–E18; n = 3; mean ± SEM; *, P < 0.05; **, P < 0.01; ***, P < 0.001; t test, two sided). (E) E13 and E15 embryonic brain sections were costained with anti–HIRA and anti–NESTIN antibodies (VZ/SVZ). Bars: (E15) 25 µm; (E13) 50 µm. (F) NPCs were costained with anti–HIRA, anti–NESTIN, anti–SOX2, and anti–PAX6 antibodies. NPCs were isolated from E12.5 mouse brains and cultured in proliferation medium for 1 d. Bar, 25 µm. (G and H) In vitro–cultured NPCs were infected with control or HIRA shRNA lentivirus, and HIRA protein levels were analyzed using Western blot. The empty control shRNA was used as a control (n = 3; mean ± SEM; ***, P < 0.01; t test, two sided). (I and J) Western blot analysis shows the overexpression of HIRA in NPCs. The empty overexpression vector was used as a control (n = 3; mean ± SEM; **, P < 0.01; t test, two sided).
Source publication
Histone cell cycle regulator (HIRA) is a histone chaperone and has been identified as an epigenetic regulator. Subsequent studies have provided evidence that HIRA plays key roles in embryonic development, but its function during early neurogenesis remains unknown. Here, we demonstrate that HIRA is enriched in neural progenitor cells, and HIRA knock...
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Citations
... SETD1A has been proposed to regulate neuronal progenitor proliferation through its interaction with Histone Cell Cycle Regulator (HIRA) (Li and Jiao, 2017) could contribute to the regulation of neuronal differentiation and excitability by transcriptionally activating β-catenin (Li and Jiao, 2017), a key component of the Wnt/β-catenin pathway which is essential for neurogenesis (Hirabayashi et al., 2004;Zhang et al., 2011;Rubio et al., 2020). In mice, a missense mutation in SETD1A resulted in faster migration of neurons within the cortex (Yu X. et al., 2019), suggesting that neuronal migration could also be regulated by SETD1A. ...
... However, divergent mechanisms could underlie a larger head size associated with loss of function mutations in SETD2 and SETD1A. For instance, deficits in SETD2 could increase NPC proliferation and lead to an enlarged brain (Li and Jiao, 2017;Shen et al., 2018;Xu et al., 2021). In contrast, loss of SETD1A might result in a macrocephalic brain due to increased neuronal arborization (Wang et al., 2022). ...
Brain size is controlled by several factors during neuronal development, including neural progenitor proliferation, neuronal arborization, gliogenesis, cell death, and synaptogenesis. Multiple neurodevelopmental disorders have co-morbid brain size abnormalities, such as microcephaly and macrocephaly. Mutations in histone methyltransferases that modify histone H3 on Lysine 36 and Lysine 4 (H3K36 and H3K4) have been identified in neurodevelopmental disorders involving both microcephaly and macrocephaly. H3K36 and H3K4 methylation are both associated with transcriptional activation and are proposed to sterically hinder the repressive activity of the Polycomb Repressor Complex 2 (PRC2). During neuronal development, tri-methylation of H3K27 (H3K27me3) by PRC2 leads to genome wide transcriptional repression of genes that regulate cell fate transitions and neuronal arborization. Here we provide a review of neurodevelopmental processes and disorders associated with H3K36 and H3K4 histone methyltransferases, with emphasis on processes that contribute to brain size abnormalities. Additionally, we discuss how the counteracting activities of H3K36 and H3K4 modifying enzymes vs. PRC2 could contribute to brain size abnormalities which is an underexplored mechanism in relation to brain size control.
... Alternatively, an age-dependent decrease in SIRT1 activity appears to be associated with abnormalities in the function of cell survival and trophic factors viz., brain-derived neurotrophic factor (BDNF), cAMP response element-binding protein (CREB), Dkk1, and Wnt that results in an aberrant cell cycle events leading to apoptosis, neurodegeneration, and impaired neurogenesis. Interestingly, recruiting H3K4 trimethyl transferase by SET Domain Containing 1A (SETD1A, Histone Lysine Methyltransferase), a chromatin remodeler of H3-Lys-4 by mono,-di-and trimethylation influencing its gene expression, stimulates -catenin activity in NSCs, thereby promoting neuronal differentiation [89]. While the failure of the canonical Wnt pathway could be regarded as a causative factor for aberrant cell cycle events leading to AD pathogenesis, considering the use of SIRT1 activators to restore and promote the activity of the Wnt pathway may hold a therapeutic key to mitigate the pathogenic signature of AD [72]. ...
Alzheimer’s disease (AD) is a major form of dementia. Abnormal amyloidogenic event-mediated degeneration of cholinergic neurons in the cognitive centers of the brain has been attributed to neuropathological sequelae and behavioral deficits in AD. Besides, impaired adult neurogenesis in the hippocampus has experimentally been realized as an underlying cause of dementia regardless of neurodegeneration. Therefore, nourishing the neurogenic process in the hippocampus has been considered an effective therapeutic strategy to mitigate memory loss. In the physiological state, the Wnt pathway has been identified as a potent mitogenic generator in the hippocampal stem cell niche. However, downstream components of Wnt signaling have been noticed to be downregulated in AD brains. Resveratrol (RSV) is a potent Sirtuin1 (SIRT1) enhancer that facilitates neuroprotection and promotes neurogenesis in the hippocampus of the adult brain. While SIRT1 is an important positive regulator of Wnt signaling, ample reports indicate that RSV treatment strongly mediates the fate determination of stem cells through Wnt signaling. However, the possible therapeutic roles of RSV-mediated SIRT1 enhancement on the regulation of hippocampal neurogenesis and reversal of memory loss through the Wnt signaling pathway have not been addressed yet. Taken together, this review describes RSV-mediated effects on the regulation of hippocampal neurogenesis via the activation of SIRT1 in synergy with the Wnt signaling. Further, the article emphasizes a hypothesis that RSV treatment can provoke the activation of quiescent neural stem cells and prime their neurogenic capacity in the hippocampus via Wnt signaling in AD.
... A previous study reported that an increased Gli3 expression can repress the Hedgehog signaling pathway in acute myeloid leukemia (Chaudhry et al., 2017). To determine whether the reduced Gli1 was attributable to an increased Gli3 in the Eed cKO forebrain, we applied a small interfering RNA (siRNA) and an overexpression plasmid to manipulate Gli3 expression in NE-4C cells, a neural stem cell-like cell line derived from embryonic neuroepithelial cells (Aprea et al., 2013;Li and Jiao, 2017). Knockdown of GLI3 led to a significant decrease of Gli3F and Gli3R and a significant increase of GLI1 protein expression ( Figure 6C). ...
Mutations in the embryonic ectoderm development (EED) cause Weaver syndrome, but whether and how EED affects embryonic brain development remains elusive. Here, we generated a mouse model in which Eed was deleted in the forebrain to investigate the role of EED. We found that deletion of Eed decreased the number of upper-layer neurons but not deeper-layer neurons starting at E16.5. Transcriptomic and genomic occupancy analyses revealed that the epigenetic states of a group of cortical neurogenesis-related genes were altered in Eed knockout forebrains, followed by a decrease of H3K27me3 and an increase of H3K27ac marks within the promoter regions. The switching of H3K27me3 to H3K27ac modification promoted the recruitment of RNA-Pol2, thereby enhancing its expression level. The small molecule activator SAG or Ptch1 knockout for activating Hedgehog signaling can partially rescue aberrant cortical neurogenesis. Taken together, we proposed a novel EED-Gli3-Gli1 regulatory axis that is critical for embryonic brain development.
... For example, a recent report found that the MLL-family methyltransferase MLL4 associates with the chromatin remodeling complex BAF , but how these two complexes couple together to regulate enhancer activation is unknown. There is also mounting evidence that HKMTs can interact with histone chaperones and histone variants to modulate chromatin structure, regulate gene expression, and maintain genome stability (Sarai et al., 2013;Li et al., 2017;Higgs et al., 2018;Ouda et al., 2018), but how HKMTs coordinate with histone chaperones remains elusive. Thus, structural studies of HKMTs in complexes with other epigenetic factors (e.g., chromatin remodeling complexes, histone chaperones, histone variants, and non-coding RNAs) will be the next frontier to reveal how these complexes act cooperatively on nucleosomes or chromatin substrates. ...
Histone lysine methyltransferases (HKMTs) deposit methyl groups onto lysine residues on histones and play important roles in regulating chromatin structure and gene expression. The structures and functions of HKMTs have been extensively investigated in recent decades, significantly advancing our understanding of the dynamic regulation of histone methylation. Here, we review the recent progress in structural studies of representative HKMTs in complex with nucleosomes (H3K4, H3K27, H3K36, H3K79, and H4K20 methyltransferases), with emphasis on the molecular mechanisms of nucleosome recognition and trans-histone crosstalk by these HKMTs. These structural studies inform HKMTs' roles in tumorigenesis and provide the foundations for developing new therapeutic approaches targeting HKMTs in cancers.
... For example, a recent report found that the MLL-family methyltransferase MLL4 associates with the chromatin remodeling complex BAF , but how these two complexes couple together to regulate enhancer activation is unknown. There is also mounting evidence that HKMTs can interact with histone chaperones and histone variants to modulate chromatin structure, regulate gene expression, and maintain genome stability (Sarai et al., 2013;Li et al., 2017;Higgs et al., 2018;Ouda et al., 2018), but how HKMTs coordinate with histone chaperones remains elusive. Thus, structural studies of HKMTs in complexes with other epigenetic factors (e.g., chromatin remodeling complexes, histone chaperones, histone variants, and non-coding RNAs) will be the next frontier to reveal how these complexes act cooperatively on nucleosomes or chromatin substrates. ...
Histone lysine methyltransferases (HKMTs) deposit methyl groups onto lysine residues on histones and play important roles in regulating chromatin structure and gene expression. The structures and functions of HKMTs have been extensively investigated in recent decades, significantly advancing our understanding of the dynamic regulation of histone methylation. Here, we review the recent progress in structural studies of representative HKMTs in complex with nucleosomes (H3K4, H3K27, H3K36, H3K79, and H4K20 methyltransferases), with emphasis on the molecular mechanisms of nucleosome recognition and trans-histone crosstalk by these HKMTs. These structural studies inform HKMTs’ roles in tumorigenesis and provide the foundations for developing new therapeutic approaches targeting HKMTs in cancers.
... H3.3 has a repressive role when trimethylated at lysine 27 at developmentally regulated bivalent domains in embryonic stem cells, suggesting an important role in differentiation 27 . Moreover, HIRA has been shown to be required for normal differentiation of various cell lineages, tissues and organs, such as neural cells, cardiomyocytes and the haematopoietic lineage [28][29][30][31][32] . HIRA and H3.3 have also been shown to play significant roles in cell and tissue aging. ...
... On the other hand, we found an increase in the expression of the TUBB3 protein (TUJ1) (Fig. 2k, m), but no effect on other tubulin isoforms (Supplementary Fig. 2m). Expression of TUBB3 has been previously associated with neural, melanocytic and EMT fates 31,[66][67][68] . (Fig. 3a), indicating the presence of functional melanocytes at this stage. ...
Histone chaperone HIRA is thought to play a role in both early development and aging, but little is known about connections between the two processes. Here, we explore this relationship using a lineage-specific knockout mouse model, TyrCre::Hira fl/fl , in which HIRA is deficient in the pigmentary system consisting of embryonic melanoblasts, postnatal melanocytes and melanocyte stem cells (McSCs). Hira knockout leads to reduced melanoblast numbers during embryogenesis, but wild type numbers of melanocytes at birth, normally functioning juvenile and young adult McSCs, and only a very mildly hypopigmented first hair coat. However, on closer analysis, Hira knockout melanocytic cells of newborn mice exhibit molecular markers characteristic of cell aging and proliferative deficits. As they age, TyrCre::Hira fl/fl mice display marked defects in McSC maintenance and premature hair graying. Importantly, these defects are only observed when HIRA is inactivated during embryogenesis, not post-natally. This genetic model illustrates how normal embryonic development lays the foundation for maintenance of adult tissue specific stem cells and so suppression of degenerative phenotypes of aging.
... HIRA expressed in embryonic cerebral cortex and NPCs, recruits H3K4 trimethyltransferase, SET Domain protein 1A (SETD1A), at the ß-catenin promoter to increase H3K4me3 level resulting in increased ß-catenin expression. Hence, perturbation of Hira leads to restricted proliferation of NPCs, increase in terminal mitosis and cell cycle exit and ultimately leads to premature neuronal differentiation (Li and Jiao, 2017). Depletion of another H3.3 chaperone, ATRX in NPCs causes replicative stress and DNA damage at telomeres and pericentric heterochromatin in mitotically active neurons (Watson et al., 2013). ...
... Melanogaster (Song et al., 2007) • Required for establishment of bilateral asymmetry and cell division in C.elegans nervous system (Nakano et al., 2011) • CAF1 in association with PCNA facilitates formation of facultative heterochromatin by silencing the pluripotency genes (Cheng et al., 2019) • Involves in heterochromatin formation in pluripotency acquisition and maintenance in ESC (Houlard et al., 2006;Zaidan et al., 2018) • Depletion of either of CAF1 P150 or CAF1 P60 enhances reprogramming capacity and iPSC generation from murine fibroblast (Cheloufi et al., 2015) and generation of totipotent 2C-like cells in vitro (Ishiuchi et al., 2015) Histone Cell Cycle Regulator (HIRA) H3.3/H4 Early embryonic lethality at E10 in M. Musculus (Roberts et al., 2002) • Decondensation of sperm chromatin during male pronucleus formation at fertilization in D. melanogaster (Bonnefoy et al., 2007) and in M.musculus (van der Heijden et al., 2005) • HIRA mediated H3.3 incorporation in gastrulation and mesoderm formation in X. laevis (Szenker et al., 2012) • Involves in regulation of cortical neurogenesis by modulating the expression of beta-catenin (Li and Jiao, 2017) • Critical regulator of hematopoiesis and heart development (Dilg et al., 2016;Chen et al., 2020) • Involves in trophectoderm lineage specification in mESC in vitro (Banaszynski et al., 2013) and in maintenance of pluripotency in hESC (Zhu et al., 2017) Anti Silencing Factor (ASF1) H3.1/H4 Asf1a null embryos dies at mid-gestation (E9.5) in M. ...
Dynamicity and flexibility of the chromatin landscape are critical for most of the DNA-dependent processes to occur. This higher-order packaging of the eukaryotic genome into the chromatin is mediated by histones and associated non-histone proteins that determine the states of chromatin. Histone chaperones- “the guardian of genome stability and epigenetic information” controls the chromatin accessibility by escorting the nucleosomal and non-nucleosomal histones as well as their variants. This distinct group of molecules is involved in all facets of histone metabolism. The selectivity and specificity of histone chaperones to the histones determine the maintenance of the chromatin in an open or closed state. This review highlights the functional implication of the network of histone chaperones in shaping the chromatin function in the development of an organism. Seminal studies have reported embryonic lethality at different stages of embryogenesis upon perturbation of some of the chaperones, suggesting their essentiality in development. We hereby epitomize facts and functions that emphasize the relevance of histone chaperones in orchestrating different embryonic developmental stages starting from gametogenesis to organogenesis in multicellular organisms.
... Suppression of Hira, but not Ubn2, uniquely activated gene ontology terms related to nervous system development and ion transport (Fig. 4g). This is consistent with a previous report that the loss of HIRA led to premature neural differentiation of neural progenitor cells [45]. In contrast, Zhang Hira shRNA1 ...
Background
Histone cell cycle regulator (HIRA) complex is an important histone chaperone that mediates the deposition of the H3.3 histone variant onto chromatin independently from DNA synthesis. However, it is still unknown whether it participates in the expression control of retrotransposons and cell fate determination.
Methods
We screened the role of HIRA complex members in repressing the expression of retrotransposons by shRNA depletion in embryonic stem cells (ESCs) followed by RT-qPCR. RNA-seq was used to study the expression profiles after depletion of individual HIRA member. RT-qPCR and western blot were used to determine overexpression of HIRA complex members. Chromatin immunoprecipitation (ChIP)-qPCR was used to find the binding of H3.3, HIRA members to chromatin. Co-immunoprecipitation was used to identify the interaction between Hira mutant and Ubn2. ChIP-qPCR was used to identify H3.3 deposition change and western blot of chromatin extract was used to validate the epigenetic change. Bioinformatics analysis was applied for the analysis of available ChIP-seq data.
Results
We revealed that Hira , Ubn2 , and Ubn1 were the main repressors of 2-cell marker retrotransposon MERVL among HIRA complex members. Surprisingly, Ubn2 and Hira targeted different groups of retrotransposons and retrotransposon-derived long noncoding RNAs (lncRNAs), despite that they partially shared target genes. Furthermore, Ubn2 prevented ESCs to gain a 2-cell like state or activate trophectodermal genes upon differentiation. Mechanistically, Ubn2 and Hira suppressed retrotransposons by regulating the deposition of histone H3.3. Decreased H3.3 deposition, that was associated with the loss of Ubn2 or Hira, caused the reduction of H3K9me2 and H3K9me3, which are known repressive marks of retrotransposons.
Conclusions
Overall, our findings shed light on the distinct roles of HIRA complex members in controlling retrotransposons and cell fate conversion in ESCs.
... Interestingly, some has suggested that HIRA-mediated H3.3 deposition may be a mechanism to maintain genomic stability when chaperone protein CAF-1 mediated H3.1 deposition is impaired during S-phase (6). Various lines of research suggest that HIRA is involved in a range of processes including embryonic development (46,47), angiogenesis (48,49), cellular senescence (50,51), and early neural development (52). ...
Canonical histone H3.1 and variant H3.3 deposit at different sites of the chromatin via distinct histone chaperones. Histone H3.1 relies on chaperone CAF-1 to mediate replication-dependent nucleosome assembly during S-phase, while H3.3 variant is regulated and incorporated into the chromatin in a replication-independent manner through HIRA and DAXX/ATRX. Current literature suggests that dysregulated expression of histone chaperones may be implicated in tumor progression. Notably, ectopic expression of CAF-1 can promote a switch between canonical H3.1 and H3 variants in the chromatin, impair the chromatic state, lead to chromosome instability, and impact gene transcription, potentially contributing to carcinogenesis. This review focuses on the chaperone proteins of H3.1 and H3.3, including structure, regulation, as well as their oncogenic and tumor suppressive functions in tumorigenesis.
... Β-catenin, the pivotal component of the Wnt pathway, is tightly regulated at many hierarchical levels, including CTNNB1 transcription, protein stability, subcellular localization and transcriptional activity of β-catenin [19]. Li et al. have reported that HIRA enhances CTNNB1 transcription by recruiting SETD1A, which increases H3K4me3 levels in the CTNNB1 promoter, thereby activating the Wnt/β-catenin pathway in neural progenitor cells [20]. Two other studies have demonstrated that SETD1A cooperates with β-catenin to activate the transcription of Wnt/β-catenin target genes in an H3K4me3dependent manner in embryonic stem cells and cancer cells [6,21]. ...
... Previous studies have proven that SETD1A promotes Wnt/β-catenin pathway activity in colorectal cancer and neural progenitor cells [6,20]. Thus, we further investigated whether SETD1A regulates cancer stem cell property and chemotherapy sensitivity in NSCLC via the Wnt/β-catenin pathway. ...
... We identified that ICAT and GSK3β expression in NSCLC cells was increased following SETD1A knockdown. As previously reported, SETD1A generally acts as a positive regulator of its target genes, whether H3K4me3-dependent or -independent [6,9,10,12,16,20]. As a result, we speculated that SETD1A probably negatively regulates ICAT and GSK3β indirectly. ...
Background
SETD1A, a member of SET1/MLL family H3K4 methyltransferases, is involved in the tumorigenesis of numerous cancers. However, the biological role and mechanism of SETD1A in non-small cell lung cancer (NSCLC) remain to be elucidated.
Methods
The expression of SETD1A, NEAT1, EZH2, and β-catenin in NSCLC tissues and cell lines was detected by qRT-PCR, immunohistochemistry and western blotting. The regulatory mechanisms were validated by chromatin immunoprecipitation, co-immunoprepitation and luciferase reporter assay. The self-renewal, cisplatin sensitivity and tumorigenesis of NSCLC cells were analyzed using sphere formation, CCK-8, colony formation assays and xenograft tumor models.
Results
SETD1A expression was significantly increased in NSCLC and its overexpression predicted a poor prognosis of patients with NSCLC. Functional experiments showed that SETD1A positively regulated cancer stem cell property and negatively regulated cisplatin sensitivity in NSCLC cells via the Wnt/β-catenin pathway. Next, we found that SETD1A positively regulated the Wnt/β-catenin pathway via interacting with and stabilizing β-catenin. The SET domain is dispensable for the interaction between SETD1A and β-catenin. Furthermore, we identified that SETD1A bound to the promoters of NEAT1 and EZH2 to activate gene transcription by inducing H3K4me3 enrichment. Rescue experiments showed that SETD1A promoted the Wnt/β-catenin pathway and exerted its oncogenic functions in NSCLC, at least, partly through NEAT1 and EZH2 upregulation. In addition, SETD1A was proven to be a direct target of the Wnt/β-catenin pathway, thus forming a positive feedback loop in NSCLC cells.
Conclusion
SETD1A and Wnt/β-catenin pathway form a positive feedback loop and coordinately contribute to NSCLC progression.
