Explore the vast range of titles available.

Interleukin-6 (IL-6) has been long considered a key player in cancer cachexia. It is believed that sustained elevation of IL-6 production during cancer progression causes brain dysfunctions, which ultimately result in cachexia. However, how peripheral IL-6 influences the brain remains poorly understood. Here we show that neurons in the area postrema (AP), a circumventricular structure in the hindbrain, is a critical mediator of IL-6 function in cancer cachexia in male mice. We find that circulating IL-6 can rapidly enter the AP and activate neurons in the AP and its associated network. Peripheral tumor, known to increase circulating IL-6, leads to elevated IL-6 in the AP, and causes potentiated excitatory synaptic transmission onto AP neurons and AP network hyperactivity. Remarkably, neutralization of IL-6 in the brain of tumor-bearing mice with an anti-IL-6 antibody attenuates cachexia and the hyperactivity in the AP network, and markedly prolongs lifespan. Furthermore, suppression of Il6ra , the gene encoding IL-6 receptor, specifically in AP neurons with CRISPR/dCas9 interference achieves similar effects. Silencing Gfral-expressing AP neurons also attenuates cancer cachectic phenotypes and AP network hyperactivity. Our study identifies a central mechanism underlying the function of peripheral IL-6, which may serve as a target for treating cancer cachexia. Elevation of IL-6 during cancer progression has been shown to drive cancer cachexia, however, while brain dysfunction has been reported, the underlying mechanism is unclear. Here, the authors identify neurons in the area postrema as a mediator of peripheral IL-6 in preclinical models of cancer cachexia.

In this Journal Club, Jessica Tollkuhn discusses how a paper describing genome-wide application of chromatin immunoprecipitation (ChIP)-on-chip inspired her own research into oestrogen-based gene regulation in the brain.

Both parents of oldfield mice care for offspring, whereas in deer mice, mothers usually care for pups. The discovery of a type of adrenal-gland cell that is present in oldfield mice but not in deer mice helps to explain the difference. Previously unknown cell type found in mice that share parental care.

Context-specific epigenetic dependencies, shaped by chromatin remodeling can create exploitable vulnerabilities for cancer therapies that are unique to tissue types and cellular identities. Here, we show that loss of BPTF (Bromodomain PHD Finger Transcription Factor), a core component of the NURF (Nucleosome Remodeling Factor) complex, results in the emergence of estrogen-responsive, tamoxifen-sensitive, Estrogen Receptor alpha (ERα) positive mammary tumors without altering cancer cell state and tumor pathology. Elevated ERα levels in BPTF mammary tumor cells are linked with decreased TGF-β activity and limited metastatic spread of mammary tumor cells to the lungs. Loss of ERα is sufficient to restore TGF-β activity and the metastatic potential in BPTF tumors. These findings highlight a mechanism through which BPTF regulates tumor development and progression in mammary epithelial cells, offering insights into the interplay between chromatin remodeling, estrogen signaling, and their resultant adjuvant therapeutic potential in breast cancer.

The POU homeodomain transcription factor Pit1 is required for pituitary development; here Pit1-occupied enhancers are shown to interact with the nuclear architecture components matrin-3 and Satb1, and this association is required for activation of Pit1-regulated enhancers and coding target genes. Enhancer activation linked to subnuclear structures The POU homeodomain transcription factor Pit1 is required for pituitary development. Here, Michael Rosenfeld and colleagues find that Pit1-occupied enhancers interact with the nuclear architecture components matrin-3 and Satb1, and this association is required for activation of Pit1-regulated genes. A disease-associated mutation in Pit1 disrupts the interaction with the matrin-3 network, leading to loss of transcriptional activity. These experiments reveal an unanticipated role for the subnuclear architecture proteins in developmental gene activation. Homeodomain proteins, described 30 years ago 1 , 2 , exert essential roles in development as regulators of target gene expression 3 , 4 ; however, the molecular mechanisms underlying transcriptional activity of homeodomain factors remain poorly understood. Here investigation of a developmentally required POU-homeodomain transcription factor, Pit1 (also known as Pou1f1), has revealed that, unexpectedly, binding of Pit1-occupied enhancers 5 to a nuclear matrin-3-rich network/architecture 6 , 7 is a key event in effective activation of the Pit1-regulated enhancer/coding gene transcriptional program. Pit1 association with Satb1 (ref. 8 ) and β-catenin is required for this tethering event. A naturally occurring, dominant negative, point mutation in human PIT1(R271W), causing combined pituitary hormone deficiency 9 , results in loss of Pit1 association with β-catenin and Satb1 and therefore the matrin-3-rich network, blocking Pit1-dependent enhancer/coding target gene activation. This defective activation can be rescued by artificial tethering of the mutant R271W Pit1 protein to the matrin-3 network, bypassing the pre-requisite association with β-catenin and Satb1 otherwise required. The matrin-3 network-tethered R271W Pit1 mutant, but not the untethered protein, restores Pit1-dependent activation of the enhancers and recruitment of co-activators, exemplified by p300, causing both enhancer RNA transcription and target gene activation. These studies have thus revealed an unanticipated homeodomain factor/β-catenin/Satb1-dependent localization of target gene regulatory enhancer regions to a subnuclear architectural structure that serves as an underlying mechanism by which an enhancer-bound homeodomain factor effectively activates developmental gene transcriptional programs.

As a key component of the vertebrate neuroendocrine system, the pituitary gland relies on the progressive and coordinated development of distinct hormone-producing cell types and an invading vascular network. The molecular mechanisms that drive formation of the pituitary vasculature, which is necessary for regulated synthesis and secretion of hormones that maintain homeostasis, metabolism, and endocrine function, remain poorly understood. Here, we report that expression of integrin β1 in embryonic pituitary epithelial cells is required for angiogenesis in the developing mouse pituitary gland. Deletion of pituitary epithelial integrin β1 before the onset of angiogenesis resulted in failure of invading endothelial cells to recruit pericytes efficiently, whereas deletion later in embryogenesis led to decreased vascular density and lumen formation. In both cases, lack of epithelial integrin β1 was associated with a complete absence of vasculature in the pituitary gland at birth. Within pituitary epithelial cells, integrin β1 directs a large transcriptional program that includes components of the extracellular matrix and associated signaling factors that are linked to the observed non–cell-autonomous effects on angiogenesis. We conclude that epithelial integrin β1 functions as a critical and canonical regulator of developmental angiogenesis in the pituitary gland, thus providing insight into the long-standing systems biology conundrum of how vascular invasion is coordinated with tissue development.

Females and males display differences in neural activity patterns, behavioral responses, and incidence of psychiatric and neurological diseases. Sex differences in the brain appear throughout the animal kingdom and are largely a consequence of the physiological requirements necessary for the distinct roles of the two sexes in reproduction. As with the rest of the body, gonadal steroid hormones act to specify and regulate many of these differences. It is thought that transient hormonal signaling during brain development gives rise to persistent sex differences in gene expression via an epigenetic mechanism, leading to divergent neurodevelopmental trajectories that may underlie sex differences in disease susceptibility. However, few genes with a persistent sex difference in expression have been identified, and only a handful of studies have employed genome-wide approaches to assess sex differences in epigenomic modifications. To date, there are no confirmed examples of gene regulatory elements that direct sex differences in gene expression in the brain. Here, we review foundational studies in this field, describe transcriptional mechanisms that could act downstream of hormone receptors in the brain, and suggest future approaches for identification and validation of sex-typical gene programs. We propose that sexual differentiation of the brain involves self-perpetuating transcriptional states that canalize sex-specific development.

Single-cell or single-nucleus transcriptomics is a powerful tool for identifying cell types and cell states. However, hypotheses derived from these assays, including gene expression information, require validation, and their functional relevance needs to be established. The choice of validation depends on numerous factors. Here, we present types of orthogonal and functional validation experiment to strengthen preliminary findings obtained using single-cell and single-nucleus transcriptomics as well as the challenges and limitations of these approaches. Single-cell or single-nucleus RNA-sequencing experiments form a basis for biological insights about cell types and states, but they require orthogonal experiments to confirm the functional relevance of their findings. Here the authors discuss options to support such findings and their challenges.

Abstract Disclosure: S.D. Sun: None. K. Yamada: None. B. Gegenhuber: None. M. Wu: None. V. Kulik: None. R. Anderson: None. M. Johnson: None. J. Tollkuhn: None. Adolescence is a neurodevelopmental critical period marked by the pubertal increase in gonadal steroid hormones (GSHs) resulting in the emergence of sex-variable behaviors. While the role of GSHs in regulating these behaviors is well described, the neurological mechanisms through which they act to direct sex-variability during adolescence remain poorly understood. We discovered that during adolescence, the GSH surge reestablishes sex-variable chromatin accessibility in brain areas that mediate several sex-variable behaviors. To assay the developmental dynamics of chromatin accessibility, we employed ATAC-seq on nuclei purified from neurons in the posterior Bed Nucleus of the Stria Terminalis (BNSTp) expressing Estrogen Receptor (ER) alpha (ERα) from mice, before (postnatal day 28), during (P35), and after (P50) the pubertal hormone surge. 3 biological replicates of 50,000 nuclei pooled from 3-5 animals were taken for each timepoint, and from multiple gonadal states (intact ovaries or testes, and prepubertal-gonadectomy controls). We found the most significantly sex-variable chromatin regions (ANOVA-like generalized linear model, FDR<0.001) exhibit several adolescently dynamic trajectories by k-means clustering. Male-biased chromatin is driven primarily by Androgen Receptor (AR) signaling and is augmented by ERα signaling. Female-biased chromatin accessibility is predominantly associated with activity-dependent signaling, not ovarian GSHs. By comparing with similar ATAC-seq experiments from gonadally-intact neonatal and juvenile mice, we identified key differences in sex-variable chromatin accessibility between the neonatal testosterone surge and adolescent activation of the gonads. Adolescently-emerging sex-variable sites are enriched for genes associated with ion channels, some of which are known to be sex-variable in expression levels during adulthood. To determine if adolescent GSH-mediated gene regulation underlies sex-variability in neurocircuit function, we employed whole-cell patch clamp ex vivo slice electrophysiology. We recorded voltage responses to current injection from a specific ERα-expressing BNSTp transcriptomic cell-type that exhibits significant male-bias in abundance and gene expression. We found that these neurons can fire action potentials at substantially higher rates in adult males, compared to adult females and prepubertal juveniles (n>4, per condition). Preliminary experiments in prepubertally gonadectomized mice suggest the adolescent emergence of high-frequency firing capacity of BNSTp neurons in male animals requires the pubertal GSH surge. Our studies describe a potential mechanism by which GSHs, through their regulation of genes that tune neuronal excitability and responsiveness, can “activate” circuits mediating sex-variable behaviors that emerge during adolescence. Presentation: Saturday, July 12, 2025

As a key component of the vertebrate neuroendocrine system, the pituitary gland relies on the progressive and coordinated development of distinct hormone-producing cell types and an invading vascular network. The molecular mechanisms that drive formation of the pituitary vasculature, which is necessary for regulated synthesis and secretion of hormones that maintain homeostasis, metabolism, and endocrine function, remain poorly understood. Here, we report that expression of integrin beta 1 in embryonic pituitary epithelial cells is required for angiogenesis in the developing mouse pituitary gland. Deletion of pituitary epithelial integrin beta 1 before the onset of angiogenesis resulted in failure of invading endothelial cells to recruit pericytes efficiently, whereas deletion later in embryogenesis led to decreased vascular density and lumen formation. In both cases, lack of epithelial integrin beta 1 was associated with a complete absence of vasculature in the pituitary gland at birth. Within pituitary epithelial cells, integrin beta 1 directs a large transcriptional program that includes components of the extracellular matrix and associated signaling factors that are linked to the observed non-cell-autonomous effects on angiogenesis. We conclude that epithelial integrin beta 1 functions as a critical and canonical regulator of developmental angiogenesis in the pituitary gland, thus providing insight into the long-standing systems biology conundrum of how vascular invasion is coordinated with tissue development.