A comparative atlas of single-cell chromatin accessibility in the human brain

Science, Год журнала: 2023, Номер 382(6667)

Опубликована: Окт. 12, 2023

Recent advances in single-cell transcriptomics have illuminated the diverse neuronal and glial cell types within human brain. However, regulatory programs governing identity function remain unclear. Using a single-nucleus assay for transposase-accessible chromatin using sequencing (snATAC-seq), we explored open landscapes across 1.1 million cells 42 brain regions from three adults. Integrating this data unveiled 107 distinct their specific utilization of 544,735 candidate cis-regulatory DNA elements (cCREs) genome. Nearly third cCREs demonstrated conservation accessibility mouse cells. We reveal strong links between neuropsychiatric disorders including schizophrenia, bipolar disorder, Alzheimer's disease (AD), major depression, developed deep learning models to predict roles noncoding risk variants these disorders.

Язык: Английский

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Developmental dynamics of RNA translation in the human brain

Nature Neuroscience, Год журнала: 2022, Номер 25(10), С. 1353 - 1365

Опубликована: Сен. 28, 2022

Язык: Английский

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Primate-specific transposable elements shape transcriptional networks during human development

Nature Communications, Год журнала: 2022, Номер 13(1)

Опубликована: Ноя. 23, 2022

Abstract The human genome contains more than 4.5 million inserts derived from transposable elements (TEs), the result of recurrent waves invasion and internal propagation throughout evolution. For new TE copies to be inherited, they must become integrated in germline or pre-implantation embryo, which requires that their source expressed at these stages. Accordingly, many TEs harbor DNA binding sites for pluripotency factors OCT4, NANOG, SOX2, KLFs are transiently during embryonic activation. Here, we describe how primate-restricted have additional lineage-specific transcription driving expression gastrulation later steps fetal development. These integrants serve as enhancers fostering transcription, amongst other targets, KRAB-zinc finger proteins (KZFPs) comparable evolutionary age, turn corral activity TE-embedded regulatory sequences a similarly lineage-restricted fashion. Thus, KZFP controllers play broad roles shaping transcriptional networks early

Язык: Английский

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Genetic features and genomic targets of human KRAB-zinc finger proteins

Genome Research, Год журнала: 2023, Номер 33(8), С. 1409 - 1423

Опубликована: Авг. 1, 2023

Krüppel-associated box (KRAB) domain-containing zinc finger proteins (KZFPs) are one of the largest groups transcription factors encoded by tetrapods, with 378 members in human alone. KZFP genes often grouped clusters reflecting amplification gene and segment duplication since family first emerged more than 400 million years ago. Previous work has revealed that many KZFPs recognize transposable element (TE)-embedded sequences as genomic targets, facilitate co-option regulatory potential TEs for benefit host. Here, we present a comprehensive survey genetic features targets KZFPs, notably completing past analyses adding data on close to hundred members. General principles emerge from our study TE-KZFP system, which point multipronged evolutionary mechanisms underlaid highly complex combinatorial modes action strong influences speciation.

Язык: Английский

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Take a walk on the KRAB side

Trends in Genetics, Год журнала: 2023, Номер 39(11), С. 844 - 857

Опубликована: Сен. 14, 2023

Язык: Английский

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Diverse heterochromatin states restricting cell identity and reprogramming

Trends in Biochemical Sciences, Год журнала: 2023, Номер 48(6), С. 513 - 526

Опубликована: Март 27, 2023

Язык: Английский

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Transposon–host arms race: a saga of genome evolution

Trends in Genetics, Год журнала: 2025, Номер unknown

Опубликована: Фев. 1, 2025

Язык: Английский

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LINE-1 activation in the cerebellum drives ataxia

Neuron, Год журнала: 2022, Номер 110(20), С. 3278 - 3287.e8

Опубликована: Сен. 6, 2022

Dysregulation of long interspersed nuclear element 1 (LINE-1, L1), a dominant class transposable elements in the human genome, has been linked to neurodegenerative diseases, but whether elevated L1 expression is sufficient cause neurodegeneration not directly tested. Here, we show that cerebellar significantly ataxia telangiectasia patients and strongly anti-correlated with epigenetic silencers. To examine role disease etiology, developed an approach for direct targeting promoter overexpression mice. We demonstrated activation cerebellum led Purkinje cell dysfunctions degeneration was ataxia. Treatment nucleoside reverse transcriptase inhibitor blunted progression by reducing DNA damage, attenuating gliosis, reversing deficits molecular regulators calcium homeostasis cells. Our study provides first evidence can drive neurodegeneration.

Язык: Английский

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A zinc finger transcription factor enables social behaviors while controlling transposable elements and immune response in prefrontal cortex

Translational Psychiatry, Год журнала: 2024, Номер 14(1)

Опубликована: Янв. 25, 2024

Abstract The neurobiological origins of social behaviors are incompletely understood. Here we utilized synthetic biology approaches to reprogram the function ZFP189, a transcription factor whose expression and in rodent prefrontal cortex was previously demonstrated be protective against stress-induced deficits. We created novel ZFP189 factors including VPR , which activates target genes therefore exerts opposite functional control from endogenous, transcriptionally repressive WT . Following viral delivery these mouse cortex, observe that ZFP189-mediated transcriptional promotes mature dendritic spine morphology on transduced pyramidal neurons. Interestingly, inversion this brain area, achieved by precipitates behavioral deficits terms interaction, motivation, cognition necessary for maintenance hierarchy, without other observable RNA sequencing virally manipulated tissues reveals opposing regulatory (ZFP189 versus ) have influence genetic transposable elements as well participate adaptive immune functions. Collectively, work coordinates structural neuroadaptations complex while regulating element-rich regions DNA immune-related genes. Given evidence co-evolution behavior response, posit may evolved augment transposon-associated way enhancing an animal’s capacity functioning groups.

Язык: Английский

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Transposable elements and their role in aging

Ageing Research Reviews, Год журнала: 2023, Номер 86, С. 101881 - 101881

Опубликована: Фев. 10, 2023

Язык: Английский

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