ARID1A-BAF coordinates ZIC2 genomic occupancy for epithelial to mesenchymal transition in cranial neural crest lineage commitment

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

Опубликована: Апрель 3, 2024

Abstract The BAF chromatin remodeler regulates lineage commitment including cranial neural crest cell (CNCC) specification. Variants in subunits cause Coffin-Siris Syndrome (CSS), a congenital disorder characterized by coarse craniofacial features and intellectual disability. Approximately 50% of CSS patients carry variants one the mutually exclusive subunits, ARID1A/ARID1B . While Arid1a deletion mouse causes severe phenotypes, little is known about role ARID1A CNCC Using patient-derived +/- iPSCs to model specification, we discovered -haploinsufficiency impairs epithelial mesenchymal transition (EMT), process necessary for delamination migration from tube. Furthermore, wild-type ARID1A-BAF enhancers associated with EMT genes. binding at these impaired heterozygotes while promoters unaffected. At sequence level, contain motifs ZIC2, ZIC2 sites ARID1A-dependent. When excluded enhancers, relocates neuronal triggering aberrant gene activation. In mice, Zic2 NCC delamination, overexpression chick embryos pre-migratory stages elicits ectopic These findings reveal novel ARID1A-ZIC2 axis essential delamination.

Язык: Английский

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Synergistic activation by Glass and Pointed promotes neuronal identity in the Drosophila eye disc

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Авг. 17, 2024

The integration of extrinsic signaling with cell-intrinsic transcription factors can direct progenitor cells to differentiate into distinct cell fates. In the developing Drosophila eye, differentiation photoreceptors R1-R7 requires EGFR mediated by factor Pointed, and our single-cell RNA-Seq analysis shows that same require eye-specific Glass. We find ectopic expression Glass activation synergistically induce neuronal gene in wing disc a Pointed-dependent manner. Targeted DamID reveals Pointed share many binding sites genome photoreceptors. Comparison transcriptomic data photoreceptor through intermediate factors, including redundant homologs Scratch Scrape, as well directly activating effector genes. Our reveal synergistic multi-layered transcriptional network mechanism which induces identity Glass-expressing cells.

Язык: Английский

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Structural and biochemical characterization of the ALX4 dimer reveals novel insights into how disease alleles impact ALX4 function

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

Опубликована: Сен. 10, 2024

1. Abstract How homeodomain proteins gain sufficient DNA binding specificity to regulate diverse processes has been a long-standing question. Here, we determine how the ALX4 Paired-like protein achieves for TAAT – NNN ATTA dimer site. We first show that binds this motif independently of its co-factor, TWIST1, in cranial neural crest cells. Structural analysis identified seven residues participate binding, many which are conserved across family, but not other proteins. Unexpectedly, two within use distinct form asymmetric protein-protein and protein-DNA interactions mediate cooperativity. Moreover, found cooperativity is required transcriptional activation disease variants cause molecular defects include loss These findings provide new insights into factors can be stratified based on their defects.

Язык: Английский

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Prediction and design of transcriptional repressor domains with large-scale mutational scans and deep learning

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

Опубликована: Сен. 24, 2024

Regulatory proteins have evolved diverse repressor domains (RDs) to enable precise context-specific repression of transcription. However, our understanding how sequence variation impacts the functional activity RDs is limited. To address this gap, we generated a high-throughput mutational scanning dataset measuring 115,000 variant sequences spanning more than 50 in human cells. We identified thousands clinical variants with loss or gain function, including TWIST1 HLH associated Saethre-Chotzen syndrome and MECP2 domain Rett syndrome. also leveraged these data annotate short linear interacting motifs (SLiMs) that are critical for disordered RDs. Then, designed deep learning model called TENet ( T ranscriptional E ffector Net work) integrates sequence, structure biochemical representations accurately predict activity. systematically tested generalization within across varying homology using dataset. Finally, employed directed evolution editing framework tune both structured experimentally test designs. Our work highlights considerations future design training strategies improve prioritization precision synthetic regulatory proteins.

Язык: Английский

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Detection of regions of homozygosity in an unusual case of frontonasal dysplasia

Molecular Cytogenetics, Год журнала: 2024, Номер 17(1)

Опубликована: Окт. 31, 2024

We present the case of a 7-year-old Ecuadorian mestizo girl with multiple orofacial malformations. The patient is product first-degree relationship (father-daughter). A cytogenetic study revealed normal karyotype. genetic mapping array identified 0.73 Gb alterations, 727,087,295 bp involved in regions homozygosity (ROH) all chromosomes (25.2% genome) and 764,028 gains 9 14. Genes from TGFB, BMP, FGF, SHH WNT families, among others, were ROH. They are related to craniofacial development their protein products showed strong association interactome analysis.

Язык: Английский

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