Biology subjects

Mosti, F.

Publications and source records attributed to Mosti, F..

5 recordsLinked to original sources

bioRxiv2025

Intraspecific sequence variation and complete genomes refine the identification of rapidly evolved regions in humans

Summary Humans exhibit significant phenotypic differences from other great apes, yet pinpointing the underlying genetic changes has been limited by incomplete reference genomes and a reliance on single assemblies to represent a species. We aligned 20 telomere-to-telomere (T2T) assemblies spanning great ape divergence and variation to define 1,596 Consensus HAQERs (consensus human ancestor quickly evolved regions), regions that diverged rapidly between the human-chimpanzee ancestor and an ancestral node of modern humans. Unlike prior HAQER sets, Consensus HAQERs incorporate population variation, reducing the likelihood of intraspecies variation appearing as interspecies divergence. Consensus HAQERs exhibit signatures of elevated mutation rates, ancient positive selection, bivalent regulatory function, are enriched in disease-linked loci, and often emerged in previously inaccessible repetitive DNA. Through multiplex, single-cell enhancer assays, we identify HAQERs as active enhancers in the developing brain and cardiomyocytes, highlighting their potential contributions to human-specific gene regulation across multiple tissues. Highlights[bullet] Telomere-to-telomere alignments of diverse human and great ape genomes identify 1,596 Consensus HAQERs, regions of rapid sequence divergence separating human ancestors from other great apes. [bullet]Consensus HAQERs exhibit signatures of both elevated mutation rates and ancient positive selection. [bullet]HAQERs are enriched in bivalent regulatory elements and disease-linked loci. [bullet]Multiplex, single-cell gene regulatory assays identify HAQERs as enhancers in the developing heart and brain.

genomics↗

bioRxiv2025

Species-specific chromatin architecture and neurogenesis mediated by a human enhancer

Genomic modifications underlie the evolution of human features, including a larger neocortex and enhanced cognition. Human Accelerated Regions (HARs) are highly-conserved loci containing human-specific variants and can act as neurodevelopmental enhancers. However, the neurodevelopmental functions of HARs and their mechanism of gene regulation are largely unknown. Here, we show that human (Hs) HAR1984 promotes neurogenesis by influencing species-specific transcription and chromatin interactions. Hs-HAR1984 knock-in chimpanzee (Pt) cortical organoids contain more progenitors and neurons, whereas Pt-HAR1984 knock-in human cortical organoids exhibit the opposite phenotype. Hs-HAR1984 knock-in mice recapitulate increased neurogenesis, producing a thicker cortex with folding. Hi-C reveals HAR1984 exhibits chromatin looping with its target genes ETV5 and TRA2B in human fetal brains, notably reduced in chimpanzee, macaque and mouse neural cells. We show that human-specific mutations in HAR1984 directly promote these interactions, favored by nearby structural variants. Further, we discover that human-specific ETV5 binding auto-regulates enhancer activity. This work demonstrates new molecular mechanisms underlying human-specific neurodevelopment, linking HARs to chromatin architecture, cortical cell fate and expansion and folding of brains.

developmental biology↗

bioRxiv2024

A human-specific enhancer fine-tunes radial glia potency and corticogenesis

Humans evolved an extraordinarily expanded and complex cerebral cortex, associated with developmental and gene regulatory modifications1-3. Human accelerated regions (HARs) are highly conserved genomic sequences with human-specific nucleotide substitutions. Although there are thousands of annotated HARs, their functional contribution to human-specific cortical development is largely unknown4,5. HARE5 is a HAR transcriptional enhancer of the WNT signaling receptor Frizzled8 (FZD8) active during brain development6. Here, using genome-edited mouse and primate models, we demonstrate that human (Hs) HARE5 fine-tunes cortical development and connectivity by controlling the proliferative and neurogenic capacity of neural progenitor cells (NPCs). Hs-HARE5 knock-in mice have significantly enlarged neocortices containing more neurons. By measuring neural dynamics in vivo we show these anatomical features correlate with increased functional independence between cortical regions. To understand the underlying developmental mechanisms, we assess progenitor fate using live imaging, lineage analysis, and single-cell RNA sequencing. This reveals Hs-HARE5 modifies radial glial progenitor behavior, with increased self-renewal at early developmental stages followed by expanded neurogenic potential. We use genome-edited human and chimpanzee (Pt) NPCs and cortical organoids to assess the relative enhancer activity and function of Hs-HARE5 and Pt-HARE5. Using these orthogonal strategies we show four human-specific variants in HARE5 drive increased enhancer activity which promotes progenitor proliferation. These findings illustrate how small changes in regulatory DNA can directly impact critical signaling pathways and brain development. Our study uncovers new functions for HARs as key regulatory elements crucial for the expansion and complexity of the human cerebral cortex.

neuroscience↗

bioRxiv2022

The RNA-binding protein EIF4A3 promotes axon development by direct control of the cytoskeleton

The exon junction complex (EJC), nucleated by EIF4A3, is indispensable for mRNA fate and function throughout eukaryotes. Unexpectedly, we discover that EIF4A3 directly controls microtubules independent of RNA, and this is critical for neural wiring. While neuronal survival in the developing mouse cerebral cortex depends upon an intact EJC, axonal tract formation requires only Eif4a3. Using human cortical organoids, we demonstrate that EIF4A3 disease mutations also impair neuronal maturation, highlighting conserved functions relevant for neurodevelopmental pathology. Employing biochemistry and molecular modeling we discover that EIF4A3 directly binds to microtubules, mutually exclusive of the RNA-binding complex. In growing neurons, EIF4A3 is essential for microtubule dynamics, and sufficient to promote microtubule polymerization and stability in vitro. Together, our data show that tubulin-bound EIF4A3 orchestrates microtubule dynamics, underlying key events of neuronal development. This reveals a new mechanism by which neurons re-utilize core gene expression machinery to rapidly and directly control the cytoskeleton. HighlightsO_LIThe Exon Junction Complex controls neuronal survival but only EIF4A3 directs axonal growth C_LIO_LIEIF4A3 controls axonal tract formation in vivo. C_LIO_LIHuman EIF4A3 deficient iPSC-derived cortical organoids recapitulate neuronal defects. C_LIO_LIEIF4A3 directly binds to microtubules to control their growth and stability in neurons. C_LI

neuroscience↗

bioRxiv2021

Translational control of polyamine metabolism by CNBP is required for Drosophila locomotor function

Microsatellite expansions of CCTG repeats in the CNBP gene leads to accumulation of toxic RNA and have been associated to DM2. However, it is still unclear whether the dystrophic phenotype is also linked to CNBP decrease, a conserved CCHC-type zinc finger RNA binding protein that regulates translation and is required for mammalian development. Here we show that depletion of Drosophila CNBP in muscles causes age-dependent locomotor defects that are correlated with impaired polyamine metabolism. We demonstrate that the levels of ornithine decarboxylase (ODC) and polyamines are significantly reduced upon dCNBP depletion. Of note, we show a reduction of the CNBP-polyamine axis in muscle from DM2 patients. Mechanistically, we provide evidence that dCNBP controls polyamine metabolism through binding dOdc mRNA and regulating its translation. Remarkably, the locomotor defect of dCNBP-deficient flies is rescued by either polyamine supplementation or dOdc1 overexpression. We suggest that this dCNBP function is evolutionarily conserved in vertebrates with relevant implications for CNBP-related pathophysiological conditions. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=195 SRC="FIGDIR/small/441910v2_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@a8c31corg.highwire.dtl.DTLVardef@1a18260org.highwire.dtl.DTLVardef@76a3d4org.highwire.dtl.DTLVardef@fdd041_HPS_FORMAT_FIGEXP M_FIG C_FIG CNBP controls muscle function by regulating the polyamine metabolism O_LILack of dCNBP impairs locomotor function through ODC-polyamine downregulation C_LIO_LIdCNBP binds dOdc mRNA and regulates its translation C_LIO_LIPolyamine supplementation or dOdc1 reconstitution rescues locomotor defects C_LIO_LICNBP-ODC-polyamine levels are reduced in muscle of DM2 patients C_LI

genetics↗