The developmental and evolutionary characteristics of transcription factor binding site clustered regions based on an explainable machine learning model

Nucleic Acids Research, Год журнала: 2024, Номер 52(13), С. 7610 - 7626

Опубликована: Май 30, 2024

Abstract Gene expression is temporally and spatially regulated by the interaction of transcription factors (TFs) cis-regulatory elements (CREs). The uneven distribution TF binding sites across genome poses challenges in understanding how this evolves to regulate spatio-temporal gene consequent heritable phenotypic variation. In study, chromatin accessibility profiles were collected from several species including mammals (human, mouse, bovine), fish (zebrafish medaka), chicken. Transcription factor clustered regions (TFCRs) at different embryonic stages characterized investigate regulatory evolution. study revealed dynamic changes TFCR during development synchronization between complexity was assessed using RegulatoryScore. Additionally, an explainable machine learning model highlighted importance distance promoter coordinated regulation TFCRs on expression. Our results developmental evolutionary dynamics fish, chicken mammals. These data provide valuable resources for exploring relationship transcriptional differences development.

Язык: Английский

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CpG island turnover events predict evolutionary changes in enhancer activity

Genome biology, Год журнала: 2024, Номер 25(1)

Опубликована: Июнь 13, 2024

Abstract Background Genetic changes that modify the function of transcriptional enhancers have been linked to evolution biological diversity across species. Multiple studies focused on role nucleotide substitutions, transposition, and insertions deletions in altering enhancer function. CpG islands (CGIs) recently shown influence activity, here we test how their turnover species contributes evolution. Results We integrate maps CGIs activity-associated histone modifications obtained from multiple tissues nine mammalian find CGI content is strongly associated with increased modification levels. show widespread species-specific are enriched for exhibiting activity all Genes concordant biases expression, supporting gene regulatory innovation. Our results also implicate Human Gain Enhancers (HGEs), which human embryonic development may contributed uniquely traits. Using a humanized mouse model, highly conserved HGE large absent ortholog shows at diencephalon. Conclusions Collectively, our point as mechanism driving potentially underlying trait mammals.

Язык: Английский

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Resolving the three-dimensional interactome of Human Accelerated Regions during human and chimpanzee neurodevelopment

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июнь 26, 2024

Abstract Human Accelerated Regions (HARs) are highly conserved across species but exhibit a significant excess of human-specific sequence changes, suggesting they may have gained novel functions in human evolution. HARs include transcriptional enhancers with activity and been implicated the evolution brain. However, our understanding how contributed to uniquely features brain is hindered by lack insight into genes pathways that regulate. It unclear whether acted altering expression gene targets between their chimpanzee orthologs or gaining new human, mechanism termed enhancer hijacking. We generated high-resolution map chromatin interactions for 1,590 neural stem cells (NSCs) comprehensively identify both species. targeted set 2,963 enriched neurodevelopmental processes including neurogenesis synaptic transmission. Changes HAR were correlated changes target expression. Conserved among differentially expressed NSCs non-human primate developing adult Species-specific did not converge on known biological significantly genes, alter via targets, also showed cell type-specific patterns brain, outer radial glia, which hypothesized contribute cortical expansion. Our findings support influenced provide means functionally link features.

Язык: Английский

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A multi-layered integrative analysis reveals a cholesterol metabolic program in outer radial glia with implications for human brain evolution

Development, Год журнала: 2024, Номер 151(16)

Опубликована: Авг. 8, 2024

ABSTRACT The definition of molecular and cellular mechanisms contributing to brain ontogenetic trajectories is essential investigate the evolution our species. Yet their functional dissection at an appropriate level granularity remains challenging. Capitalizing on recent efforts that have extensively profiled neural stem cells from developing human cortex, we develop integrative computational framework perform trajectory inference gene regulatory network reconstruction, (pseudo)time-informed non-negative matrix factorization for learning dynamics expression programs, paleogenomic analysis a higher-resolution mapping derived variants in species comparison with closest relatives. We provide evidence cell type-specific regulation programs during indirect neurogenesis. In particular, uncovers key role cholesterol program outer radial glia, regulated by zinc-finger transcription factor KLF6. A cartography landscape impacted Homo sapiens-derived reveals signals selection clustering around regions associated GLI3, well-known regulator glial cycle, impacting KLF6 regulation. Our study contributes significant changes metabolic pathways evolution.

Язык: Английский

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Detection and analysis of complex structural variation in human genomes across populations and in brains of donors with psychiatric disorders

Cell, Год журнала: 2024, Номер 187(23), С. 6687 - 6706.e25

Опубликована: Сен. 30, 2024

Язык: Английский

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