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. 2022 May 4;606(7912):153–159. doi: 10.1038/s41586-022-04686-1

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© The Author(s) 2022

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 2 — a, Uniform manifold approximation and projection (UMAP) visualization of BNSTp Esr1+ snRNA-seq inhibitory neuron clusters, coloured by identity (left), sex (middle) and Esr1 expression (right). b, Proportion of BNSTp Esr1+ nuclei in each BNSTp Esr1+ inhibitory neuron cluster per sex. Higher proportions of i1:Nfix (P_adj = 0.002) and i3:Esr2 (P_adj = 0.002) neurons are in males than females. Boxplot centre, median; box boundaries, first and third quartiles; whiskers, 1.5 × IQR from boundaries, n = 7, **P_adj < 0.01, one-sided, Wilcoxon rank-sum test, adjusted with the Benjamini–Hochberg procedure. c, BNSTp immunofluorescence (IF) staining for GFP (left micrographs) and Nfix (middle micrographs) in P14 female and male Esr1^Cre/+;Sun1–GFP^lx/+ animals (scale bar, 100 µm), with combined images (right micrographs) and their quantification (boxplots; right). Boxplot centre, median; box boundaries, first and third quartiles; whiskers, 1.5 × IQR from boundaries, n = 6, P = 0.0422, *P < 0.05, two-sided, unpaired t-test. d, Heatmap of median MetaNeighbor area under the receiver operating characteristic curve (AUROC) values for BNSTp Esr1+ clusters and cortical/hippocampal GABAergic neuron subclasses. The colour bar indicates the developmental origin of GABAergic subclasses. CGE, caudal ganglionic eminence; MGE, medial ganglionic eminence. e, Top: heatmap of MetaNeighbor AUROC values for BNSTp and MPOA Esr1+ clusters. Bottom: average expression of i1:Nfix marker genes across BNSTp and MPOA Esr1+ clusters. Dotted box indicates shared identity of i1:Nfix and i20:Gal.Moxd1 cells. n = 297 i20:Gal.Moxd1 cells, 2,459 i1:Nfix cells. Boxplot centre, median; box boundaries, first and third quartiles; whiskers, 1.5 × IQR from boundaries. f, Number of differentially expressed genes (DEGs) between females and males (DESeq2, P_adj < 0.1) per BNST neuron snRNA-seq cluster. g, R² between percentage of TF gene expression and number of sex DEGs per cluster across snRNA-seq clusters. The inset shows correlation for the top-ranked TF gene, Esr1. The error band represents the 95% confidence interval. h, Differential ATAC sites between gonadectomized (GDX), vehicle-treated females and males (top) and gonadally intact females and males (middle). Blue dots (edgeR, log₂[FC] > 1, P_adj < 0.05), red dots (edgeR, log₂[FC] < −1, P_adj < 0.05). Bottom: enrichment analysis of sex-biased ATAC peaks at sex DEGs. i, Top: k-means clustering (c1–c4) of differentially accessible ATAC peaks across four conditions(edgeR, P_adj < 0.01). Bottom: dotplot showing the percentage of sites per cluster overlapping E2-open ATAC loci and motif enrichment analysis of peaks in each cluster (AME algorithm). ARE, androgen response element. j, Example ATAC peaks in k-means clusters 1 and 2. Top left number is the y-axis range in CPM. Shaded band indicates peak region.

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