Biology subjects

Picketts, D. J.

Publications and source records attributed to Picketts, D. J..

4 recordsLinked to original sources

bioRxiv2026

ISWI remodeler facilitates cBAF genomic binding to drive cell fate transition

The ISWI chromatin remodeler regulates nucleosome spacing using one of two ATPase subunits Snf2h (Smarca5) and Snf2l (Smarca1). While Snf2h stable knockout (KO) is known to markedly reduce genomic binding of CTCF, an architectural protein organizing the 3D genome, ISWIs role in regulating genomic binding and function of lineage-determining transcription factors (LDTFs) during cell fate transition remains largely unclear. Using conditional KO mice and derived cells, we show Snf2h and Snf2l are partially redundant and are required for embryonic development of muscle and adipose tissue as well as myogenesis and adipogenesis in culture. Stable KO of ISWI impairs LDTF-stimulated cell differentiation and disrupts de novo binding of the myogenic LDTF MyoD and the cBAF chromatin remodeler. Surprisingly, acute depletion of ISWI leaves de novo MyoD binding landscape largely intact while disrupting MyoD-dependent recruitment of cBAF and CTCF, with minimal effects on constitutive genomic binding of cBAF and CTCF. Together, our findings identify ISWI as an important mediator connecting LDTF binding to cBAF recruitment and chromatin organization during cell fate transition. Bullet points- ISWI ATPases Snf2h and Snf2l are partially redundant and essential for muscle and adipose development - ISWI is required for MyoD, C/EBP, and PPAR{gamma}-driven cell fate transition - Stable KO of ISWI disrupts genomic binding of MyoD, while acute depletion does not - Acute ISWI deletion disrupts MyoD-dependent, but not constitutive, genomic binding of cBAF and CTCF

cell biology↗

bioRxiv2025

The SMARCA5-DMRT1 Pioneer Complex Establishes Epigenetic Priming to Direct Male Germline Development

The establishment of cell type-specific chromatin landscapes is essential for cellular identity, but how these landscapes are generated remains poorly understood. Here, we demonstrate that the chromatin remodeler SMARCA5 establishes epigenetic priming that is required for retinoic acid (RA)-induced differentiation in the male germline. Germ cell-specific deletion of Smarca5 results in a complete loss of differentiating spermatogonia, phenocopying vitamin A-deficient mice that lack RA signaling. During the perinatal transition from prospermatogonia to undifferentiated spermatogonia, SMARCA5 is recruited to binding sites of the pioneer transcription factor DMRT1, which are located at distal putative enhancers and promoters of germline genes. The SMARCA5-DMRT1 pioneer complex establishes chromatin accessibility at these loci, generating poised enhancers and promoters that serve as RA receptor (RAR)-binding sites. Thus, SMARCA5 licenses transcriptional responses to RA that enable spermatogenic differentiation. Our findings uncover a mechanism linking pioneer factor activity to external signal responsiveness. HighlightsSMARCA5 is required for spermatogonial differentiation The SMARCA5-DMRT1 pioneer complex establishes epigenetic priming for differentiation SMARCA5 remodels inaccessible DMRT1-binding sites to an accessible state SMARCA5 shapes chromatin states that enable retinoic acid responsiveness

developmental biology↗

bioRxiv2024

The ChAHP chromatin remodelling complex regulates neurodevelopmental disorder risk genes to scale the production of neocortical layers

Although chromatin remodellers are among the most important risk genes associated with neurodevelopmental disorders (NDDs), the roles of these complexes during brain development are in many cases unclear. Here, we focused on the recently discovered ChAHP chromatin remodelling complex. The zinc finger and homeodomain transcription factor ADNP is a core subunit of this complex, and de novo ADNP mutations lead to intellectual disability and autism spectrum disorder. However, germline Adnp knockout mice were previously shown to exhibit early embryonic lethality, obscuring subsequent roles for the ChAHP complex in neurogenesis. Here, we employed single cell transcriptomics, cut&run-seq, and histological approaches to characterize mice conditionally ablated for the ChAHP subunits Adnp and Chd4. We show that during neocortical development, Adnp and Chd4 orchestrate the production of late-born, upper-layer neurons through a two-step process. First, Adnp is required to sustain progenitor proliferation specifically during the developmental window for upper-layer cortical neurogenesis. Accordingly, we found that Adnp recruits Chd4 to genes associated with progenitor proliferation. Second, in postmitotic differentiated neurons, we define a network of risk genes linked to NDDs that are regulated by Adnp and Chd4. Taken together, these data demonstrate that ChAHP is critical for driving the expansion upper-layer cortical neurons, and for regulating neuronal gene expression programs, suggesting that these processes may potentially contribute to NDD etiology. HighlightsO_LIAdnp and Chd4 cKOs exhibit similar deficits in cortical growth C_LIO_LIAdnp sustains the proliferation of apical progenitors to scale the production of upper-layer neurons C_LIO_LIAdnp recruits Chd4 to genes involved in corticogenesis C_LIO_LIAdnp is a master regulator of risk genes associated with neurodevelopmental disorders C_LI

neuroscience↗

bioRxiv2023

A new mouse model of ATR-X syndrome carrying a common patient mutation exhibits neurological and morphological defects

ATRX is a chromatin remodelling ATPase that is involved in transcriptional regulation, DNA damage repair and heterochromatin maintenance. It has been widely studied for its role in ALT-positive cancers, but its role in neurological function remains elusive. Hypomorphic mutations in the X-linked ATRX gene cause a rare form of intellectual disability combined with alpha-thalassemia called ATR-X syndrome in hemizygous males. Patients also have facial dysmorphism, microcephaly, musculoskeletal defects and genital abnormalities. Since complete deletion of ATRX in mice results in early embryonic lethality, the field has largely relied on conditional knockout models to assess the role of ATRX in multiple tissues. Given that null alleles are not found in patients, a more patient-relevant model was needed. Here, we have produced and characterised the first patient mutation knock-in model of ATR-X syndrome, carrying the most common patient mutation, R246C. This is one of a cluster of missense mutations located in the chromatin interaction domain that disrupts its function. The knock-in mice recapitulate several aspects of the patient disorder, including craniofacial defects, microcephaly and impaired neurological function. They provide a powerful model for understanding the molecular mechanisms underlying ATR-X syndrome and for testing potential therapeutic strategies.

neuroscience↗