Transposable elements and their KZFP controllers are drivers of transcriptional innovation in the developing human brain

Genome Research, Год журнала: 2021, Номер 31(9), С. 1531 - 1545

Опубликована: Авг. 16, 2021

Transposable elements (TEs) account for more than 50% of the human genome and many have been co-opted throughout evolution to provide regulatory functions gene expression networks. Several lines evidence suggest that these networks are fine-tuned by largest family TE controllers, KRAB-containing zinc finger proteins (KZFPs). One tissue permissive transcriptional activation (termed “transposcription”) is adult brain, however comprehensive studies on extent this process its potential contribution brain development lacking. To elucidate spatiotemporal transposcriptome developing we analyzed two independent RNA-seq data sets encompassing 16 regions from eight weeks postconception into adulthood. We reveal a distinct KZFP:TE profile defining late prenatal early postnatal transition, cell type–specific TE-derived alternative promoters driving neurogenesis-associated genes. Long-read sequencing confirmed TE-driven isoforms as significant contributors neurogenic transcripts. also show experimentally antisense L2 element drives temporal protein relocalization away endoplasmic reticulum, suggestive novel dependent function in primate evolution. This work highlights widespread dynamic nature transcriptome importance mediated innovation neurotypical development. facilitate interactive exploration dynamics, “Brain TExplorer” web application freely accessible community.

Язык: Английский

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RNA splicing regulators play critical roles in neurogenesis

Wiley Interdisciplinary Reviews - RNA, Год журнала: 2022, Номер 13(6)

Опубликована: Апрель 6, 2022

Abstract Alternative RNA splicing increases transcript diversity in different cell types and under varying conditions. It is executed with the help of regulators (RSRs), which are operationally defined as RNA‐binding proteins (RBPs) that regulate alternative splicing, but not directly catalyzing chemical reactions splicing. By systematically searching for RBPs manually identifying those we curated 305 RSRs human genome. Surprisingly, most involved neurogenesis. Among these RSRs, focus on nine families (PTBP, NOVA, RBFOX, ELAVL, CELF, DBHS, MSI, PCBP, MBNL) play essential roles neurogenic pathway. A better understanding their functions will provide novel insights into role brain development, health, disease. This comprehensive review serves a stepping‐stone to explore diverse complex set fundamental neural development. article categorized under: RNA‐Based Catalysis > Splicing Translation Interactions Proteins Other Molecules Protein‐RNA Interactions: Functional Implications Processing Regulation/Alternative

Язык: Английский

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Mice in translational neuroscience: What R we doing?

Progress in Neurobiology, Год журнала: 2022, Номер 217, С. 102330 - 102330

Опубликована: Июль 21, 2022

Animal models play a pivotal role in translational neuroscience but recurrent problems data collection, analyses, and interpretation, lack of biomarkers, tendency to over-reliance on mice have marred progress, leading one the highest attrition rates drug translation. Global initiatives improve reproducibility model selection are being implemented. Notwithstanding, still preferred animal species human brain disorders even when translation has been shown be limited. Non-human primates better positioned provide relevant information because their higher complexity homology humans. Among others, resources formal training, strict legislation, ethical issues may impede broad access large animals. We propose that instead increasingly restrictive more for education, husbandry, sharing urgently needed. The creation multidisciplinary teams, which veterinarians need key role, would critical efficiency. Furthermore, it is not usually acknowledged by researchers regulators value comparative studies lower species, instrumental toxicology, target identification, mechanistic studies. Overall, we highlight here conceptual shift research policies reach patients.

Язык: Английский

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Single-cell and long-read sequencing to enhance modelling of splicing and cell-fate determination

Computational and Structural Biotechnology Journal, Год журнала: 2023, Номер 21, С. 2373 - 2380

Опубликована: Янв. 1, 2023

Single-cell sequencing technologies have revolutionised the life sciences and biomedical research. provides high-resolution data on cell heterogeneity, allowing high-fidelity type identification, lineage tracking. Computational algorithms mathematical models been developed to make sense of data, compensate for errors simulate biological processes, which has led breakthroughs in our understanding differentiation, cell-fate determination tissue composition. The development long-read (a.k.a. third-generation) produced powerful tools investigating alternative splicing, isoform expression (at RNA level), genome assembly detection complex structural variants DNA level).In this review, we provide an overview recent advancements single-cell technologies, with a particular focus computational that help correcting, analysing, interpreting resulting data. Additionally, review some use study respectively. Moreover, highlight emerging opportunities modelling result from combination technologies.

Язык: Английский

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Therapeutic strategies for autism: targeting three levels of the central dogma of molecular biology

Translational Psychiatry, Год журнала: 2023, Номер 13(1)

Опубликована: Фев. 16, 2023

Abstract The past decade has yielded much success in the identification of risk genes for Autism Spectrum Disorder (ASD), with many studies implicating loss-of-function (LoF) mutations within these genes. Despite this, no significant clinical advances have been made so far development therapeutics ASD. Given role LoF ASD etiology, are designed to rescue haploinsufficient effect at transcriptional, translational, and protein levels. This review will discuss various therapeutic techniques being developed from each level central dogma examples including: CRISPR activation (CRISPRa) gene replacement DNA level, antisense oligonucleotides (ASOs) mRNA small-molecule drugs followed by a current delivery methods therapeutics. Since nervous system (CNS) penetrance is utmost importance therapeutics, it especially necessary evaluate that higher efficiency crossing blood-brain barrier (BBB).

Язык: Английский

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Proteoforms expand the world of microproteins and short open reading frame-encoded peptides

iScience, Год журнала: 2023, Номер 26(2), С. 106069 - 106069

Опубликована: Янв. 27, 2023

Microproteins and short open reading frame-encoded peptides (SEPs) can, like all proteins, carry numerous posttranslational modifications. Together with posttranscriptional processes, this leads to a high number of possible distinct protein molecules, the proteoforms, out limited genes. The identification, quantification, molecular characterization proteoforms possess special challenges established, mainly bottom-up proteomics (BUP) based analytical approaches. While BUP methods are powerful, proteins have be inferred rather than directly identified, which hampers detection proteoforms. An alternative approach is top-down (TDP) allows identify intact This perspective article provides brief overview modified microproteins SEPs, introduces proteoform terminology, compares present TDP workflows highlighting their major advantages caveats. Necessary future developments in fully accentuate its potential for proteoform-centric analytics SEPs will discussed.

Язык: Английский

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Contribution of A-to-I RNA editing, M6A RNA Methylation, and Alternative Splicing to physiological brain aging and neurodegenerative diseases

Mechanisms of Ageing and Development, Год журнала: 2023, Номер 212, С. 111807 - 111807

Опубликована: Апрель 5, 2023

Aging is a physiological and progressive phenomenon in all organisms' life cycle, characterized by the accumulation of degenerative processes triggered several alterations within molecular pathways. These changes compromise cell fate, resulting loss functions tissues throughout body, including brain. Physiological brain aging has been linked to structural functional alterations, as well an increased risk neurodegenerative diseases. Post-transcriptional RNA modifications modulate mRNA coding properties, stability, translatability, expanding capacity genome, are involved cellular processes. Among post-transcriptional modifications, A-to-I editing, m6A Methylation Alternative Splicing play critical role phases neuronal cycle their mechanisms action significantly contribute neurodegeneration. Here we review our current understanding contribution Methylation, process

Язык: Английский

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The omics era: a nexus of untapped potential for Mendelian chromatinopathies

Human Genetics, Год журнала: 2023, Номер 143(4), С. 475 - 495

Опубликована: Апрель 28, 2023

Abstract The OMICs cascade describes the hierarchical flow of information through biological systems. epigenome sits at apex cascade, thereby regulating RNA and protein expression human genome governs cellular identity function. Genes that regulate epigenome, termed epigenes, orchestrate complex signaling programs drive development. broad patterns epigenes during development mean pathogenic germline mutations in can lead to clinically significant multi-system malformations, developmental delay, intellectual disabilities, stem cell dysfunction. In this review, we refer disorders caused by epigene mutation as “chromatinopathies”. We curated largest number chromatinopathies date our expanded approach more than doubled established 179 148 epigenes. Our study revealed 20.6% (148/720) cause least one chromatinopathy. highlight key examples which approaches have been applied chromatinopathy patient biospecimens identify underlying disease pathogenesis. rapidly evolving technologies couple molecular biology with high-throughput sequencing or proteomics allow us dissect out causal mechanisms driving temporal-, cellular-, tissue-specific expression. Using full repertoire data generated will provide invaluable insight into impact these point toward future precision targets for rare disorders.

Язык: Английский

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Single-cell long-read sequencing in human cerebral organoids uncovers cell-type-specific and autism-associated exons

Cell Reports, Год журнала: 2023, Номер 42(11), С. 113335 - 113335

Опубликована: Окт. 26, 2023

Dysregulation of alternative splicing has been repeatedly associated with neurodevelopmental disorders, but the extent cell-type-specific in human neural development remains largely uncharted. Here, single-cell long-read sequencing induced pluripotent stem cell (iPSC)-derived cerebral organoids identifies over 31,000 uncatalogued isoforms and 4,531 events. Long reads uncover coordinated intron retention events, which are challenging to study short reads. Retained neuronal introns enriched RNA regulators, showing shorter lengths, higher GC contents, weaker 5′ splice sites. We use this dataset explore biological processes underlying neurological focusing on autism. In comparison prior transcriptomic data, we find that program autistic brains is closer progenitor state than differentiated neurons. Furthermore, exons harbor significantly more de novo mutations autism probands siblings. Overall, these results highlight importance gene regulation.

Язык: Английский

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Large-scale assessment of pros and cons of autopsy-derived or tumor-matched tissues as the norms for gene expression analysis in cancers

Computational and Structural Biotechnology Journal, Год журнала: 2023, Номер 21, С. 3964 - 3986

Опубликована: Янв. 1, 2023

Normal tissues are essential for studying disease-specific differential gene expression. However, healthy human controls typically available only in postmortal/autopsy settings. In cancer research, fragments of pathologically normal tissue adjacent to tumor site frequently used as the controls. it is largely underexplored how cancers can systematically influence expression neighboring tissues. Here we performed a comprehensive pan-cancer comparison molecular profiles solid tumor-adjacent and autopsy-derived "healthy" We found number systemic differences related activation immune cells, intracellular transport autophagy, cellular respiration, telomerase activation, p38 signaling, cytoskeleton remodeling, reorganization extracellular matrix. The were deficient apoptotic signaling negative regulation cell growth including G2/M cycle transition checkpoint. also detected an extensive rearrangement chemical perception network. Molecular targets 32 37 drugs over- or underexpressed, respectively, norms. These processes may be driven by events that correlated between paired tissues, mostly relate inflammation pathways such p38, MAPK, Notch, IGF1 signaling. using model macaque postmortal showed 30 minutes – 24-hour time frame at 4ºC, RNA degradation pattern lung biosamples resulted artifact "differential" profile 1140 genes, although no could liver. Thus, concerns should addressed practice.

Язык: Английский

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