PRC2.1- and PRC2.2-specific accessory proteins drive recruitment of different forms of canonical PRC1.

Polycomb repressive complex 2 (PRC2) mediates H3K27me3 deposition, which is thought to recruit canonical PRC1 (cPRC1) via chromodomain-containing CBX proteins to promote stable repression of developmental genes. PRC2 forms two major subcomplexes, PRC2.1 and PRC2.2, but their specific roles remain unclear. Through genetic knockout (KO) and replacement of PRC2 subcomplex-specific subunits in naïve and primed pluripotent cells, we uncover distinct roles for PRC2.1 and PRC2.2 in mediating the recruitment of different forms of cPRC1. PRC2.1 catalyzes the majority of H3K27me3 at Polycomb target genes and is sufficient to promote recruitment of CBX2/4-cPRC1 but not CBX7-cPRC1. Conversely, while PRC2.2 is poor at catalyzing H3K27me3, we find that its accessory protein JARID2 is essential for recruitment of CBX7-cPRC1 and the consequent 3D chromatin interactions at Polycomb target genes. We therefore define distinct contributions of PRC2.1- and PRC2.2-specific accessory proteins to Polycomb-mediated repression and uncover a new mechanism for cPRC1 recruitment.

Molecular adaptations of the blood-brain barrier promote stress resilience vs. depression.

Preclinical and clinical studies suggest that inflammation and vascular dysfunction contribute to the pathogenesis of major depressive disorder (MDD). Chronic social stress alters blood-brain barrier (BBB) integrity through loss of tight junction protein claudin-5 (cldn5) in male mice, promoting passage of circulating proinflammatory cytokines and depression-like behaviors. This effect is prominent within the nucleus accumbens, a brain region associated with mood regulation; however, the mechanisms involved are unclear. Moreover, compensatory responses leading to proper behavioral strategies and active resilience are unknown. Here we identify active molecular changes within the BBB associated with stress resilience that might serve a protective role for the neurovasculature. We also confirm the relevance of such changes to human depression and antidepressant treatment. We show that permissive epigenetic regulation of cldn5 expression and low endothelium expression of repressive cldn5-related transcription factor foxo1 are associated with stress resilience. Region- and endothelial cell-specific whole transcriptomic analyses revealed molecular signatures associated with stress vulnerability vs. resilience. We identified proinflammatory TNFα/NFκB signaling and hdac1 as mediators of stress susceptibility. Pharmacological inhibition of stress-induced increase in hdac1 activity rescued cldn5 expression in the NAc and promoted resilience. Importantly, we confirmed changes in HDAC1 expression in the NAc of depressed patients without antidepressant treatment in line with CLDN5 loss. Conversely, many of these deleterious CLDN5-related molecular changes were reduced in postmortem NAc from antidepressant-treated subjects. These findings reinforce the importance of considering stress-induced neurovascular pathology in depression and provide therapeutic targets to treat this mood disorder and promote resilience.

Neurobiology of resilience in depression: immune and vascular insights from human and animal studies.

Major depressive disorder (MDD) is a chronic and recurrent psychiatric condition characterized by depressed mood, social isolation and anhedonia. It will affect 20% of individuals with considerable economic impacts. Unfortunately, 30-50% of depressed individuals are resistant to current antidepressant treatments. MDD is twice as prevalent in women and associated symptoms are different. Depression's main environmental risk factor is chronic stress, and women report higher levels of stress in daily life. However, not every stressed individual becomes depressed, highlighting the need to identify biological determinants of stress vulnerability but also resilience. Based on a reverse translational approach, rodent models of depression were developed to study the mechanisms underlying susceptibility vs resilience. Indeed, a subpopulation of animals can display coping mechanisms and a set of biological alterations leading to stress resilience. The aetiology of MDD is multifactorial and involves several physiological systems. Exacerbation of endocrine and immune responses from both innate and adaptive systems are observed in depressed individuals and mice exhibiting depression-like behaviours. Increasing attention has been given to neurovascular health since higher prevalence of cardiovascular diseases is found in MDD patients and inflammatory conditions are associated with depression, treatment resistance and relapse. Here, we provide an overview of endocrine, immune and vascular changes associated with stress vulnerability vs. resilience in rodents and when available, in humans. Lack of treatment efficacy suggests that neuron-centric treatments do not address important causal biological factors and better understanding of stress-induced adaptations, including sex differences, could contribute to develop novel therapeutic strategies including personalized medicine approaches.