The role of histone modifications: from neurodevelopment to neurodiseases

Park, Jisu; Lee, Kyubin; Kim, Kyunghwan; Yi, Sun‐Ju

doi:10.1038/s41392-022-01078-9

Cited by 126 publications

(72 citation statements)

References 283 publications

(257 reference statements)

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“…Dynamic changes in chromatin structure are a prominent pathological feature of neurodegenerative diseases, progeroid syndromes, cardiac hypertrophy and heart failure [ 34 , 35 , 36 , 37 ]. Notably, increased heterochromatin condensation mediated by H3K9 try-methylation correlates with transcriptional dysfunction and neurodegeneration in animal models of HD and human HD patients [ 10 ].…”

Section: Discussionmentioning

confidence: 99%

Longevity-Associated Variant of BPIFB4 Confers Neuroprotection in the STHdh Cell Model of Huntington Disease

Cattaneo

Maciąg

Milella

et al. 2022

IJMS

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Huntington’s disease (HD) is caused by the production of mutant Huntingtin (mHTT), characterized by long polyglutamine repeats with toxic effects. There are currently no clinically validated therapeutic agents that slow or halt HD progression, resulting in a significant clinical unmet need. The striatum-derived STHdh cell line, generated from mHTT knock-in mouse embryos (STHdhQ111/Q111), represents a useful model to study mechanisms behind pathogenesis of HD and to investigate potential new therapeutic targets. Indeed, these cells show susceptibility to nucleolar stress, activated DNA damage response and apoptotic signals, and elevated levels of H3K9me3 that all together concur in the progressive HD pathogenesis. We have previously shown that the adeno-associated viral vector-mediated delivery of the longevity-associated variant (LAV) of BPIFB4 prevents HD progression in a mouse model of HD. Here, we show that LAV-BPIFB4 stably infected in STHdhQ111/Q111 cells reduces (i) nucleolar stress and DNA damage through the improvement of DNA repair machinery, (ii) apoptosis, through the inhibition of the caspase 3 death signaling, and (iii) the levels of H3K9me3, by accelerating the histone clearance, via the ubiquitin–proteasome pathway. These findings pave the way to propose LAV-BPIFB4 as a promising target for innovative therapeutic strategies in HD.

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Section: Discussionmentioning

confidence: 99%

Longevity-Associated Variant of BPIFB4 Confers Neuroprotection in the STHdh Cell Model of Huntington Disease

Cattaneo

Maciąg

Milella

et al. 2022

IJMS

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“…Therefore, we could not test for a correlation between DNA-methylation and gene expression for the XIST gene. In addition to DNA-methylation, other mechanisms participate in gene regulation, for example, histone modifications [ 57 , 58 ], alteration in transcription factor binding sites [ 59 , 60 ], miRNAs [ 57 , 61 ], and alternative splicing [ 62 , 63 ]. In this regard, these regulatory mechanisms have previously been found to be associated with MDD and LOAD.…”

Section: Discussionmentioning

confidence: 99%

“…For example, histone deacetylases (HDAC) have been associated with MDD and LOAD. Hdac5 expression was lowered in the nucleus accumbens in an MDD mouse model [ 57 ], while HDAC2 and HDAC6 levels were elevated in LOAD [ 58 ]. HDAC2 reduces the acetylation of genes tied to learning and memory, and HDAC6 plays a role in increasing phosphorylated tau [ 58 ].…”

Section: Discussionmentioning

confidence: 99%

“…Hdac5 expression was lowered in the nucleus accumbens in an MDD mouse model [ 57 ], while HDAC2 and HDAC6 levels were elevated in LOAD [ 58 ]. HDAC2 reduces the acetylation of genes tied to learning and memory, and HDAC6 plays a role in increasing phosphorylated tau [ 58 ]. Another transcription regulator is the alteration of transcription factor binding sites, which have been found to be altered by SNPs found in both MDD and LOAD GWAS [ 59 , 60 ].…”

Section: Discussionmentioning

confidence: 99%

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Differential Gene Expression and DNA Methylation in the Risk of Depression in LOAD Patients

et al. 2022

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Depression is common among late-onset Alzheimer’s Disease (LOAD) patients. Only a few studies investigated the genetic variability underlying the comorbidity of depression in LOAD. Moreover, the epigenetic and transcriptomic factors that may contribute to comorbid depression in LOAD have yet to be studied. Using transcriptomic and DNA-methylomic datasets from the ROSMAP cohorts, we investigated differential gene expression and DNA-methylation in LOAD patients with and without comorbid depression. Differential expression analysis did not reveal significant association between differences in gene expression and the risk of depression in LOAD. Upon sex-stratification, we identified 25 differential expressed genes (DEG) in males, of which CHI3L2 showed the strongest upregulation, and only 3 DEGs in females. Additionally, testing differences in DNA-methylation found significant hypomethylation of CpG (cg20442550) on chromosome 17 (log2FC = −0.500, p = 0.004). Sex-stratified differential DNA-methylation analysis did not identify any significant CpG probes. Integrating the transcriptomic and DNA-methylomic datasets did not discover relationships underlying the comorbidity of depression and LOAD. Overall, our study is the first multi-omics genome-wide exploration of the role of gene expression and epigenome alterations in the risk of comorbid depression in LOAD patients. Furthermore, we discovered sex-specific differences in gene expression underlying the risk of depression symptoms in LOAD.

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“…Histones are proteins that have an essential structural and functional significance in the transition between active and inactive states in chromatin and are responsible for gene regulation and epigenetic silencing [ 107 , 108 ]. The chromatin organization involves two copies of each of the histone H2A, H2B, H3, and H4 proteins, forming a central structured globular domain with a close connection with the DNA [ 109 , 110 ] and a less well-structured amino-terminal tail domain [ 111 , 112 ].…”

Section: Role Of Post-translational Modification Of Dna-associated Hi...mentioning

confidence: 99%

Molecular Insights into Epigenetics and Cannabinoid Receptors

Basavarajappa

Subbanna²

2022

Biomolecules

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The actions of cannabis are mediated by G protein-coupled receptors that are part of an endogenous cannabinoid system (ECS). ECS consists of the naturally occurring ligands N-arachidonylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG), their biosynthetic and degradative enzymes, and the CB1 and CB2 cannabinoid receptors. Epigenetics are heritable changes that affect gene expression without changing the DNA sequence, transducing external stimuli in stable alterations of the DNA or chromatin structure. Cannabinoid receptors are crucial candidates for exploring their functions through epigenetic approaches due to their significant roles in health and diseases. Epigenetic changes usually promote alterations in the expression of genes and proteins that can be evaluated by various transcriptomic and proteomic analyses. Despite the exponential growth of new evidence on the critical functions of cannabinoid receptors, much is still unknown regarding the contribution of various genetic and epigenetic factors that regulate cannabinoid receptor gene expression. Recent studies have identified several immediate and long-lasting epigenetic changes, such as DNA methylation, DNA-associated histone proteins, and RNA regulatory networks, in cannabinoid receptor function. Thus, they can offer solutions to many cellular, molecular, and behavioral impairments found after modulation of cannabinoid receptor activities. In this review, we discuss the significant research advances in different epigenetic factors contributing to the regulation of cannabinoid receptors and their functions under both physiological and pathological conditions. Increasing our understanding of the epigenetics of cannabinoid receptors will significantly advance our knowledge and could lead to the identification of novel therapeutic targets and innovative treatment strategies for diseases associated with altered cannabinoid receptor functions.

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The role of histone modifications: from neurodevelopment to neurodiseases

Cited by 126 publications

References 283 publications

Longevity-Associated Variant of BPIFB4 Confers Neuroprotection in the STHdh Cell Model of Huntington Disease

Longevity-Associated Variant of BPIFB4 Confers Neuroprotection in the STHdh Cell Model of Huntington Disease

Differential Gene Expression and DNA Methylation in the Risk of Depression in LOAD Patients

Molecular Insights into Epigenetics and Cannabinoid Receptors

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