Chromatin accessibility and transcription dynamics during in vitro astrocyte differentiation of Huntington’s Disease Monkey pluripotent stem cells

Goodnight, Alexandra V.; Kremsky, Isaac; Khampang, Sujittra; Jung, Younghun; Billingsley, James M.; Bosinger, Steven E.; Corcés, Victor G.; Chan, Anthony W.S.

doi:10.1186/s13072-019-0313-6

Cited by 10 publications

(7 citation statements)

References 148 publications

(200 reference statements)

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“…However, these models may be altered by the type of mutations as well as by the frequency of the suggested modifiers in the populations, and this might explain the effect of ethnicity and might also indicate an indirect effect of the environment over genetics (Kousi and Katsanis, 2015;Bis-Brewer and Züchner, 2018;Amin et al, 2021). Numerous studies have also suggested an impact of epigenetics in Parkinson's, Alzheimer's, Huntington's diseases, cerebellar ataxias (CA), and ALS (Chestnut et al, 2011;Desplats et al, 2011;Chouliaras et al, 2013;Goodnight et al, 2019;Haertle et al, 2019;Jia et al, 2019;Lardenoije et al, 2019). A role for epigenetics in apoptosis was suggested in motor neuron pathology in ALS, with the upregulation of DNA methylase increasing DNA methylation which results in apoptosis (Chestnut et al, 2011).…”

Section: Genetic Diagnosis: Approaches Yield and Gap In Genetic Etiologymentioning

confidence: 99%

Insights into Clinical, Genetic, and Pathological Aspects of Hereditary Spastic Paraplegias: A Comprehensive Overview

Elsayed

Eltazi

Ahmed

et al. 2021

Front. Mol. Biosci.

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Hereditary spastic paraplegias (HSP) are a heterogeneous group of motor neurodegenerative disorders that have the core clinical presentation of pyramidal syndrome which starts typically in the lower limbs. They can present as pure or complex forms with all classical modes of monogenic inheritance reported. To date, there are more than 100 loci/88 spastic paraplegia genes (SPG) involved in the pathogenesis of HSP. New patterns of inheritance are being increasingly identified in this era of huge advances in genetic and functional studies. A wide range of clinical symptoms and signs are now reported to complicate HSP with increasing overall complexity of the clinical presentations considered as HSP. This is especially true with the emergence of multiple HSP phenotypes that are situated in the borderline zone with other neurogenetic disorders. The genetic diagnostic approaches and the utilized techniques leave a diagnostic gap of 25% in the best studies. In this review, we summarize the known types of HSP with special focus on those in which spasticity is the principal clinical phenotype (“SPGn” designation). We discuss their modes of inheritance, clinical phenotypes, underlying genetics, and molecular pathways, providing some observations about therapeutic opportunities gained from animal models and functional studies. This review may pave the way for more analytic approaches that take into consideration the overall picture of HSP. It will shed light on subtle associations that can explain the occurrence of the disease and allow a better understanding of its observed variations. This should help in the identification of future biomarkers, predictors of disease onset and progression, and treatments for both better functional outcomes and quality of life.

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Section: Genetic Diagnosis: Approaches Yield and Gap In Genetic Etiologymentioning

confidence: 99%

Insights into Clinical, Genetic, and Pathological Aspects of Hereditary Spastic Paraplegias: A Comprehensive Overview

Elsayed

Eltazi

Ahmed

et al. 2021

Front. Mol. Biosci.

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“…In addition, E2F1 regulates cell cycle gene transcription in a H2AZ- and BET bromodomain protein-dependent manner in melanoma and GBM [ 14 , 17 , 28 ]. There also appears to be a connection between chromatin accessibility at E2F target genes and cell identity as it decreases when wing and pluripotent stem cells differentiate and exit from cell cycle [ 29 , 30 ]. Collectively, these observations raise the possibility that E2Fs may regulate H2AZ gene transcription, which in turn affect cell proliferation and stemness of GSC.…”

Section: Introductionmentioning

confidence: 99%

E2F and STAT3 provide transcriptional synergy for histone variant H2AZ activation to sustain glioblastoma chromatin accessibility and tumorigenicity

et al. 2022

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The histone variant H2AZ is overexpressed in diverse cancer types where it facilitates the accessibility of transcriptional regulators to the promoters of cell cycle genes. However, the molecular basis for its dysregulation in cancer remains unknown. Here, we report that glioblastomas (GBM) and glioma stem cells (GSCs) preferentially overexpress H2AZ for their proliferation, stemness and tumorigenicity. Chromatin accessibility analysis of H2AZ2 depleted GSC revealed that E2F1 occupies the enhancer region within H2AZ2 gene promoter, thereby activating H2AZ2 transcription. Exploration of other H2AZ2 transcriptional activators using a customized “anti-H2AZ2” query signature for connectivity map analysis identified STAT3. Co-targeting E2F and STAT3 synergistically reduced the levels of H2AZ, histone 3 lysine 27 acetylation (H3K27ac) and cell cycle gene transcription, indicating that E2F1 and STAT3 synergize to activate H2AZ gene transcription in GSCs. Remarkably, an E2F/STAT3 inhibitor combination durably suppresses GSC tumorigenicity in an orthotopic GBM xenograft model. In glioma patients, high STAT3 signaling is associated with high E2F1 and H2AZ2 expression. Thus, GBM has uniquely opted the use of E2F1- and STAT3-containing “enhanceosomes” that integrate multiple signaling pathways to achieve H2AZ gene activation, supporting a translational path for the E2F/STAT3 inhibitor combination to be applied in GBM treatment.

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“…For this, we retrieved 14 studies and 79 datasets (Table 5; Supplementary Figure S1). Among 14 studies, 12 were related to mouse models (Ng et al, 2013;Vashishtha et al, 2013;Crotti et al, 2014;Mielcarek et al, 2014;Achour et al, 2015;Langfelder et al, 2016;Miller et al, 2016;Handley et al, 2017;Jacobsen et al, 2017;Pan et al, 2018;Goodnight et al, 2019;Radulescu et al, 2019;Yildirim et al, 2019;Lee et al, 2020;Wertz et al, 2020), one study was related to sheep (Handley et al, 2017) and one to monkey (Goodnight et al, 2019).…”

Section: Transcriptional Changes In Non-human Modelsmentioning

confidence: 99%

“…In early stage, genes such as Clspn, Gpr153, Gpx6, Krt9, Penk and Plk5 were frequently dysregulated, while in intermediate stage, Penk, Atp2b1, Scn4b, TABLE 5 | Characteristics of included non human HD studies. The table summarizes the PMID, sample, cell type, reference and key findings of each included non human study (Ng et al, 2013;Vashishtha et al, 2013;Crotti et al, 2014;Mielcarek et al, 2014;Langfelder et al, 2016;Handley et al, 2017;Jacobsen et al, 2017;Pan et al, 2018;Goodnight et al, 2019;Radulescu et al, 2019;Yildirim et al, 2019;Lee et al, 2020;Wertz et al, 2020). Pde10a and Rbfox1 were dysregulated to name a few.…”

Section: Transcriptional Changes In Non-human Modelsmentioning

confidence: 99%

A Systematic Review of Transcriptional Dysregulation in Huntington’s Disease Studied by RNA Sequencing

et al. 2021

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Huntington’s disease (HD) is a chronic neurodegenerative disorder caused by an expansion of polyglutamine repeats in exon 1 of the Huntingtin gene. Transcriptional dysregulation accompanied by epigenetic alterations is an early and central disease mechanism in HD yet, the exact mechanisms and regulators, and their associated gene expression programs remain incompletely understood. This systematic review investigates genome-wide transcriptional studies that were conducted using RNA sequencing (RNA-seq) technology in HD patients and models. The review protocol was registered at the Open Science Framework (OSF). The biomedical literature and gene expression databases, PubMed and NCBI BioProject, Array Express, European Nucleotide Archive (ENA), European Genome-Phenome Archive (EGA), respectively, were searched using the defined terms specified in the protocol following the PRISMA guidelines. We conducted a complete literature and database search to retrieve all RNA-seq-based gene expression studies in HD published until August 2020, retrieving 288 articles and 237 datasets from PubMed and the databases, respectively. A total of 27 studies meeting the eligibility criteria were included in this review. Collectively, comparative analysis of the datasets revealed frequent genes that are consistently dysregulated in HD. In postmortem brains from HD patients, DNAJB1, HSPA1B and HSPB1 genes were commonly upregulated across all brain regions and cell types except for medium spiny neurons (MSNs) at symptomatic disease stage, and HSPH1 and SAT1 genes were altered in expression in all symptomatic brain datasets, indicating early and sustained changes in the expression of genes related to heat shock response as well as response to misfolded proteins. Specifically in indirect pathway medium spiny neurons (iMSNs), mitochondria related genes were among the top uniquely dysregulated genes. Interestingly, blood from HD patients showed commonly differentially expressed genes with a number of brain regions and cells, with the highest number of overlapping genes with MSNs and BA9 region at symptomatic stage. We also found the differential expression and predicted altered activity of a set of transcription factors and epigenetic regulators, including BCL6, EGR1, FOSL2 and CREBBP, HDAC1, KDM4C, respectively, which may underlie the observed transcriptional changes in HD. Altogether, our work provides a complete overview of the transcriptional studies in HD, and by data synthesis, reveals a number of common and unique gene expression and regulatory changes across different cell and tissue types in HD. These changes could elucidate new insights into molecular mechanisms of differential vulnerability in HD.Systematic Review Registration:https://osf.io/pm3wq

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Chromatin accessibility and transcription dynamics during in vitro astrocyte differentiation of Huntington’s Disease Monkey pluripotent stem cells

Cited by 10 publications

References 148 publications

Insights into Clinical, Genetic, and Pathological Aspects of Hereditary Spastic Paraplegias: A Comprehensive Overview

Insights into Clinical, Genetic, and Pathological Aspects of Hereditary Spastic Paraplegias: A Comprehensive Overview

E2F and STAT3 provide transcriptional synergy for histone variant H2AZ activation to sustain glioblastoma chromatin accessibility and tumorigenicity

A Systematic Review of Transcriptional Dysregulation in Huntington’s Disease Studied by RNA Sequencing

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