Regulatory networks of KRAB zinc finger genes and transposable elements changed during human brain evolution and disease

Published: Jan. 13, 2025

Evidence indicates that transposable elements (TEs) can contribute to the evolution of new traits, despite often being considered deleterious. In vertebrates, some KRAB-ZNF proteins repress TEs, offering genomic protection. Notably, genes evolve rapidly and exhibit diverse expression patterns in primate brains, where TEs remain active. This prompts questions about their interactions brains potential roles human brain disease. For a systematic comparative analysis TE with other genes, we developed tool TEKRABber, focused on strong experimentally validated cases. Our bipartite network revealed significantly more between humans than primates, especially recently evolved, i.e. Simiiformes specific, TEs. ZNF528, under positive selection humans, shows numerous human-specific interactions. Most negative our network, indicative repression by proteins, entail Alu while links are generally positive. Alzheimer’s patients, subnetwork involving 21 an module appears diminished or lost. findings suggest vary across families, have increased throughout evolution, may influence susceptibility

Language: Английский

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Regulatory networks of KRAB zinc finger genes and transposable elements changed during human brain evolution and disease

Published: Jan. 13, 2025

Evidence indicates that transposable elements (TEs) can contribute to the evolution of new traits, despite often being considered deleterious. In vertebrates, some KRAB-ZNF proteins repress TEs, offering genomic protection. Notably, genes evolve rapidly and exhibit diverse expression patterns in primate brains, where TEs remain active. This prompts questions about their interactions brains potential roles human brain disease. For a systematic comparative analysis TE with other genes, we developed tool TEKRABber, focused on strong experimentally validated cases. Our bipartite network revealed significantly more between humans than primates, especially recently evolved, i.e. Simiiformes specific, TEs. ZNF528, under positive selection humans, shows numerous human-specific interactions. Most negative our network, indicative repression by proteins, entail Alu while links are generally positive. Alzheimer’s patients, subnetwork involving 21 an module appears diminished or lost. findings suggest vary across families, have increased throughout evolution, may influence susceptibility

Language: Английский

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Comparative Genomics Reveals LINE-1 Recombination with Diverse RNAs

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 3, 2025

ABSTRACT Long interspersed element-1 (LINE-1, L1) retrotransposons are the most abundant protein-coding transposable elements (TE) in mammalian genomes, and have shaped genome content over 170 million years of evolution. LINE-1 is self-propagating mobilizes other sequences, including Alu elements. Occasionally, forms chimeric insertions with non-coding RNAs mRNAs. U6 spliceosomal small nuclear RNA/LINE-1 chimeras best known, though there no comprehensive catalogs chimeras. To address this, we developed TiMEstamp, a computational pipeline that leverages multiple sequence alignments (MSA) to estimate age identify candidate where an adjacent arrives contemporaneously. Candidates were refined by detecting hallmark features L1 retrotransposition, such as target site duplication (TSD). Applying this human genome, recovered all known species discovered new involving RNAs, elements, mRNA fragments. Some compatible mechanisms, RNA ligation. Other structures nominate novel trans-splicing. We also see evidence loci defunct promoters can acquire regulatory from nearby genes restore retrotransposition activity. These discoveries highlight recombinatory potential implications for evolution TE domestication. GRAPHICAL

Language: Английский

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Jumping in the human brain: A review on somatic transposition

Fundamental Research, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

Language: Английский

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Probing enzyme-dependent pseudouridylation using direct RNA sequencing to assess epitranscriptome plasticity in a neuronal cell line

Cell Systems, Journal Year: 2025, Volume and Issue: unknown, P. 101238 - 101238

Published: March 1, 2025

Language: Английский

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Transposon expression and repression in skeletal muscle

Mobile DNA, Journal Year: 2025, Volume and Issue: 16(1)

Published: April 11, 2025

Language: Английский

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Young transposable elements rewired gene regulatory networks in human and chimpanzee hippocampal intermediate progenitors

Development, Journal Year: 2022, Volume and Issue: 149(19)

Published: Sept. 2, 2022

ABSTRACT The hippocampus is associated with essential brain functions, such as learning and memory. Human hippocampal volume significantly greater than expected compared that of non-human apes, suggesting a recent expansion. Intermediate progenitors, which are able to undergo multiple rounds proliferative division before final neurogenic division, may have played role in evolutionary To investigate the evolution gene regulatory networks underpinning neurogenesis we leveraged differentiation human chimpanzee induced pluripotent stem cells into TBR2 (or EOMES)-positive intermediate progenitor (hpIPCs). We found active hpIPCs different between humans chimpanzees, ∼2500 genes being differentially expressed. demonstrate species-specific transposon-derived enhancers contribute these transcriptomic differences. Young transposons, predominantly endogenous retroviruses SINE-Vntr-Alus (SVAs), were co-opted manner. Human-specific SVAs provided substrates for thousands novel TBR2-binding sites, CRISPR-mediated repression attenuated expression ∼25% upregulated progenitors relative same cell population chimpanzee.

Language: Английский

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ZFP92, a KRAB domain zinc finger protein enriched in pancreatic islets, binds to B1/Alu SINE transposable elements and regulates retroelements and genes

PLoS Genetics, Journal Year: 2023, Volume and Issue: 19(5), P. e1010729 - e1010729

Published: May 8, 2023

Repressive KRAB domain-containing zinc-finger proteins (KRAB-ZFPs) are abundant in mammalian genomes and contribute both to the silencing of transposable elements (TEs) regulation developmental stage- cell type-specific gene expression. Here we describe studies zinc finger protein 92 (Zfp92), an X-linked KRAB-ZFP that is highly expressed pancreatic islets adult mice, by analyzing global Zfp92 knockout (KO) mice. Physiological, transcriptomic genome-wide chromatin binding indicate principal function ZFP92 mice bind suppress activity B1/Alu type SINE modulate surrounding genomic entities. Deletion leads changes expression select LINE LTR retroelements genes located vicinity ZFP92-bound chromatin. The absence altered specific islets, adipose muscle result modest sex-specific alterations blood glucose homeostasis, body mass fat accumulation. In influences concentration postnatal via transcriptional effects on Mafb, whereas muscle, it regulates Acacb, a rate-limiting enzyme fatty acid metabolism. Zfp92, novel TE-Capn11 fusion transcript overexpressed several other tissues due de-repression IAPez TE adjacent intron 3 Capn11 gene. Together, these show functions repress TEs regulate transcription discrete tissues.

Language: Английский

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Non‐coding regulatory elements: Potential roles in disease and the case of epilepsy

Neuropathology and Applied Neurobiology, Journal Year: 2021, Volume and Issue: 48(3)

Published: Nov. 25, 2021

Abstract Non‐coding DNA (ncDNA) refers to the portion of genome that does not code for proteins and accounts greatest physical proportion human genome. ncDNA includes sequences are transcribed into RNA molecules, such as ribosomal RNAs (rRNAs), microRNAs (miRNAs), long non‐coding (lncRNAs) un‐transcribed have regulatory functions, including gene promoters enhancers. Variation in regions an established role disease, with growing evidence from many areas, several cancers, Parkinson's disease autism. Here, we review features functions elements present these disease. We then existing research epilepsy emphasise potential value further exploring epilepsy. In addition, outline most widely used techniques recognising throughout genome, current methodologies investigating variation main challenges associated field DNA.

Language: Английский

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Investigation of chimeric transcripts derived from LINE-1 and Alu retrotransposons in cerebellar tissues of individuals with autism spectrum disorder (ASD)

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: Sept. 19, 2024

Language: Английский

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