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. 2021 Oct 6;598(7879):86–102. doi: 10.1038/s41586-021-03950-0

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© The Author(s) 2021

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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Extended Data Fig. 6 — a, Detection of putative enhancer-gene pairs. 7,245 pairs of positively correlated cCRE and genes (highlighted in red) were identified using an empirically defined significance threshold of FDR < 0.01. Grey filled curve shows the distribution of PCC for randomly shuffled cCRE-gene pairs. b, Heatmap of chromatin accessibility of 6,280 putative enhancers, grouped by distinct enhancer-gene modules, across joint cell clusters (left) and expression of 2,490 target genes (right). Note genes are displayed for each putative enhancer separately. CPM: counts per million, TPM: transcripts per million. About 76% of putative enhancers showed cluster-specific chromatin accessibility and were enriched for lineage-specific TFs, while 24% were widely accessible and linked to genes expressed across neuronal clusters with the highest expression in glutamatergic neurons (module M1). Other modules (M2 to M14) of enhancer-gene pairs were active in a subclass-specific manner. c, Enrichment of known TF motifs in distinct enhancer-gene modules. Displayed are known motifs from HOMER with enrichment -log p-value > 10. In module M1, de novo motif analysis of putative enhancers showed enrichment of sequence motifs recognized by TFs CTCF and MEF2. CTCF is a widely expressed DNA binding protein with a well-established role in transcriptional insulation and chromatin organization, but recently it was also reported that CTCF can promote neurogenesis by binding to promoters and enhancers of related genes. In the L2/3 IT selective module M2, putative enhancers were enriched for the binding motif for Zinc-finger transcription factor EGR, a known master transcriptional regulator of excitatory neurons⁸⁹. In the Pvalb selective module M8, putative enhancers were enriched for sequence motifs recognized by the MADS factor MEF2, which is associated with regulating cortical inhibitory and excitatory synapses and behaviours relevant to neurodevelopmental disorders⁹⁰. d, Heatmap showing the weight of each joint cell cluster in each module, derived from the coefficient matrix. The values of each column are scaled (0–1).