Egr1 is a sex-specific regulator of neuronal chromatin, synaptic plasticity, and behaviour

Rocks, Devin; Purisic, Eric; Gallo, Eduardo F.; Greally, John M.; Suzuki, Masako; Kundakovic, Marija

doi:10.1101/2023.12.20.572697

Cited by 3 publications

(1 citation statement)

References 72 publications

(159 reference statements)

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“…While not all neurons may use this switch-type regulation, we note that the female hippocampus shows rhythms in dendritic spine number and synaptic density which follow the 4-5 day oestrous cycle (Jaric et al , 2019; Shors et al , 2001; Woolley & McEwen, 1992). The molecular mechanisms may even be similar with the mammalian Sr ortholog Egr1 linked to these changes in plasticity in female hippocampal neurons (Rocks et al , 2023).…”

Section: Discussionmentioning

confidence: 99%

Circadian clock neurons use activity-regulated gene expression for structural plasticity

Lymer,

Patel,

Lennon

et al. 2024

Preprint

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Drosophila s-LNv circadian pacemaker neurons show dramatic structural plasticity, with their projections expanded at dawn and then retracted by dusk. This predictable plasticity makes s-LNvs ideal to study molecular mechanisms of plasticity. Although s-LNv plasticity is controlled by their molecular clock, changing s-LNv excitability also regulates plasticity. Here, we tested the idea that s-LNvs use activity-regulated genes to control plasticity. We found that inducing expression of either of the activity-regulated transcription factors Hr38 or Sr (orthologs of mammalian Nr4a1 and Egr1) is sufficient to rapidly expand s-LNv projections. Conversely, transiently knocking down expression of either Hr38 or sr blocks expansion of s-LNv projections at dawn. We show that Hr38 rapidly induces transcription of sif, which encodes a Rac1 GEF required for s-LNv plasticity rhythms. We conclude that the s-LNv molecular clock controls s-LNv excitability, which couples to an activity-regulated gene expression program to control s-LNv plasticity.

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Section: Discussionmentioning

confidence: 99%

Circadian clock neurons use activity-regulated gene expression for structural plasticity

Lymer,

Patel,

Lennon

et al. 2024

Preprint

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Epigenomic landscape of the human dorsal root ganglion: sex differences and transcriptional regulation of nociceptive genes

Franco-Enzástiga,

Inturi,

Natarajan

et al. 2024

Preprint

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Gene expression is influenced by chromatin architecture via controlled access of regulatory factors to DNA. To better understand regulation of gene expression in the human dorsal root ganglion (hDRG) we used bulk and spatial transposase-accessible chromatin technology followed by sequencing (ATAC-seq). We detected a total of 3005 differentially accessible chromatin regions (DARs) between sexes using bulk ATAC-seq. DARs in female hDRG mapped mainly to the X chromosome. In males, DARs were found in autosomal genes. We also found differential transcription factor binding motifs within DARs. EGR1/3 and SP1/4 were abundant in females, and JUN, FOS and other AP-1 family members in males. With the aim of dissecting the open chromatin profile in hDRG neurons, we used spatial ATAC-seq. Consistent with our bulk ATAC-seq data, most of the DARs in female hDRG were located in X chromosome genes. Neuron cluster showed higher chromatin accessibility in GABAergic, glutamatergic, and interferon-related genes in females, and in Ca2+-signaling-related genes in males. Sex differences in open chromatin transcription factor binding sites in neuron-proximal barcodes were consistent with the bulk data, having EGR1 transcription factor activity in females and AP-1 family members in males. Accordingly, we showed higher expression of EGR1 in female hDRG compared to male with in-situ hybridization. Our findings point to epigenomic sex differences in the hDRG that likely underlie divergent transcriptional responses that determine mechanistic sex differences in pain.

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Spatially-resolved molecular sex differences at single cell resolution in the adult human hypothalamus

Mulvey,

Wang,

Divecha

et al. 2024

Preprint

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The hypothalamus contains multiple regions, including the ventromedial hypothalamus (VMH) and arcuate (ARC), which are responsible for sex-differentiated functions such as endocrine signaling, metabolism, and reproductive behaviors. While molecular, anatomic, and sex-differentiated features of rodent hypothalamus are well-established, much less is known about these regions in humans. Here we provide a spatially-resolved single cell atlas of sex-differentially expressed (sex-DE) genes in human VMH and ARC. We identify neuronal populations governing hypothalamus-specific functions, define their spatial distributions, and show increased retinoid pathway gene expression compared to rodents. Within VMH and ARC, we find correlated autosomal expression differences localized to ESR1/TAC3-expressing and CRHR2-expressing neurons, and extensive sex-DE of genes linked to sex-biased disorders including autism, depression, and schizophrenia. Our molecular mapping of disease associations to hypothalamic cell types with established roles in sex-divergent physiology and behavior provides insights into mechanistic bases of sex bias in neurodevelopmental and neuropsychiatric disorders.

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Egr1 is a sex-specific regulator of neuronal chromatin, synaptic plasticity, and behaviour

Cited by 3 publications

References 72 publications

Circadian clock neurons use activity-regulated gene expression for structural plasticity

Circadian clock neurons use activity-regulated gene expression for structural plasticity

Epigenomic landscape of the human dorsal root ganglion: sex differences and transcriptional regulation of nociceptive genes

Spatially-resolved molecular sex differences at single cell resolution in the adult human hypothalamus

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