Abstract P116: Specific Chromatin Configurations Across The Genome Determine The Renin Cell Identity

Abstract

Renin cell descendants, such as smooth muscle cells, regain the endocrine renin phenotype to overcome homeostatic threats. The mechanism involved and the determinants of the renin cell identity are not well understood. We hypothesize that renin cell identity is governed by specific chromatin domain configurations genome wide. We compared open chromatin regions between renin- and non-renin-expressing cells. Non-renin control ATAC-seq data were mainly from ENCODE, containing 178 samples of 26 cell types. The differential analyses with DESeq2 between three renin groups (renin-expressing tumoral cell lines, native and recruited renin cells) and non-renin control group revealed that the chromatin configurations are different between the tumoral cell line and the primary kidney cells (native and recruited) in 1) number of differential regions (22,321 increased accessibility regions in the tumoral cell lines and 3,964 in the primary kidney renin cells); 2) enriched GO terms, and 3) distribution pattern over the genome. Within a small proportion of overlapped differential accessibility regions, all three groups have accessibility regions associated with known renin-specific genes: Ren1 and Akr1b7. The motif enrichment analyses with the MEME suite on the increased accessibility regions show different sets of enriched transcription factor (TF) motifs between the tumoral cell line and primary cells. The top enriched motifs in the tumoral cell line are the bZip family, including Atf3 (q-value: 2.56e-2147), Fos (q-value: 1.01e-2406), and JunB (q-value: 8.73e-2432). The top enriched motifs in the primary cells are the MEF2 family, including MEF2a (q-value: 2.18e-91), MEF2c (q-value: 1.28e-80), and MEF2d (q-value: 1.28e-80), consistent with unpublished work in our lab. In addition, we found four topmost enriched motifs (MEIS1, NR4A2, FOXJ3, and NR4A1, with q-values of 8.24e-10, 9.78e-9, 3.96e-7, and 2.67e-6) co-enriched in regions associated with Ren1 and Akr1b7. This indicates that a set of TFs regulates the co-expressing of Ren1 and Akr1b7. The chromatin domains and TF we described are likely to control renin cell identity and may serve as therapeutic targets for kidney/vascular diseases and hypertension.