The rapid elimination of dying neurons and nonfunctional synapses in the brain is carried out by microglia, the resident myeloid cells of the brain. Here we show that microglia clearance activity in the adult brain is regionally regulated and depends on the rate of neuronal attrition. Cerebellar, but not striatal or cortical, microglia exhibited high levels of basal clearance activity, which correlated with an elevated degree of cerebellar neuronal attrition. Exposing forebrain microglia to apoptotic cells activated gene-expression programs supporting clearance activity. We provide evidence that the polycomb repressive complex 2 (PRC2) epigenetically restricts the expression of genes that support clearance activity in striatal and cortical microglia. Loss of PRC2 leads to aberrant activation of a microglia clearance phenotype, which triggers changes in neuronal morphology and behavior. Our data highlight a key role of epigenetic mechanisms in preventing microglia-induced neuronal alterations that are frequently associated with neurodegenerative and psychiatric diseases.

We report locus-specific disintegration of megabase-scale chromosomal conformations in brain after neuronal ablation of Kmt1e/Setdb1 histone H3-lysine 9 methyltransferase, including a large topologically associated 1.2Mb domain conserved in human and mouse and encompassing >70 genes at the clustered Protocadherin (cPcdh) locus. TADcPcdh in mutant neurons showed abnormal accumulations of CTCF transcriptional regulator and 3D genome organizer at cryptic binding sites, converted into permissive state with DNA cytosine hypomethylation and histone hyperacetylation. Broadly upregulated expression across cPcdh included defective S-type Protocadherin single-cell stochastic constraint. Setdb1-dependent loop formations, bypassing 0.2–1Mb of linear genome, radiated from TADPcdh fringes towards cPcdh cis-regulatory sequences, counterbalanced shorter-range facilitative promoter-enhancer contacts and carried loop-bound polymorphisms associated with genetic risk for schizophrenia. We show that KRAB-zinc finger Setdb1 repressor complex, shielding neuronal 3D genomes from excess CTCF binding, is critically required for structural maintenance of TADcPcdh.

Chicana/Latina undergraduate students represent a significant and growing proportion of student enrollment in higher education institutions in the United States, particularly in states like California that have critical masses of Chicanx/Latinx communities. Despite their increasing enrollment rates, Chicana/Latina college students continue to experience racial/ethnic and gendered isolation, academic and culture shock, feelings of imposter syndrome, and a lack of belonging at the university. This article applied Anzaldúa's theoretical concept of nepantla to the college transition experiences of 18 Chicana/Latina mujeres who participated in a Summer Bridge program at a research-intensive, public 4-year university in Southern California. Through interview and focus group data, we found that Chicana/Latina students were constantly negotiating their racial and gendered identities with their new college student identities. The clash between their former realities and new realities positioned them as atravesadas within a university context that questioned their aptitude for higher education, which detrimentally impacted their perception of themselves as students. The fusing of their old and new realities led the Chicana/Latina students in our study to form a new, complex, and informed reality that emerged from their old and new worlds on their own terms and through their own understanding of collegiate success. Given these mujer-centered findings, this article challenges the linearity and assimilationist undertones of leading college transition frameworks and models that are unfit to explain the ongoing transition experiences of Chicanas/Latinas. Further, this article advances an understanding of the transition to college for Chicana/Latina students that is mujer-centered, multidimensional, and fluid.