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Kidney Int., Nov 02 2023, S0085-2538(23)00757-3 | https://doi.org/10.1016/j.kint.2023.09.030 Chromatin accessibility analysis and architectural profiling of human kidneys reveal key cell types and a regulator of diabetic kidney disease

Minho Eun ^1†, Donggun Kim ^1†, So-I Shin ¹, Hyun Oh Yang ², Kyoung-Dong Kim ², Sin Young Choi ¹, Sehoon Park ³, Kyung Chul Moon ⁴, Dong Ki Kim ^3,5, Hajeong Lee ^3,5, Jihwan Park¹

¹School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, Republic of Korea

²Department of Systems Biotechnology, Chung-Ang University, Anseong, Republic of Korea

³Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea

⁴Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea

⁵Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea

^†These authors contributed equally to this work

Correspondence: Hajeong Lee, MD, PhD, Jihwan Park

Abstract

Diabetes is the leading cause of kidney disease that progresses to kidney failure. However, the key molecular and cellular pathways involved in diabetic kidney disease (DKD) pathogenesis are largely unknown. Here, we performed a comparative analysis of adult human kidneys by examining cell type-specific chromatin accessibility by single-nucleus ATAC-seq (snATAC-seq) and analyzing three-dimensional chromatin architecture via high-throughput chromosome conformation capture (Hi-C method) of paired samples. We mapped the cell type-specific and DKD-specific open chromatin landscape and found that genetic variants associated with kidney diseases were significantly enriched in the proximal tubule- (PT) and injured PT-specific open chromatin regions in samples from patients with DKD. BACH1 was identified as a core transcription factor of injured PT cells; its binding target genes were highly associated with fibrosis and inflammation, which were also key features of injured PT cells. Additionally, Hi-C analysis revealed global chromatin architectural changes in DKD, accompanied by changes in local open chromatin patterns. Combining the snATAC-seq and Hi-C data identified direct target genes of BACH1, and indicated that BACH1 binding regions showed increased chromatin contact frequency with promoters of their target genes in DKD. Thus, our multi-omics analysis revealed BACH1 target genes in injured PTs and highlighted the role of BACH1 as a novel regulator of tubular inflammation and fibrosis.

논문정보

형식Research article
게재일2023년 11월 (BRIC 등록일 2023-11-06)
연구진국내 연구진
분야 생명과학 > 분자생물학

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