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Deletion of NuRD component Mta2 in nephron progenitor cells causes developmentally programmed FSGS [2month.ChIPseq]

ABSTRACT: Low nephron endowment at birth is a risk factor for chronic kidney disease. The prevalence of this condition is increasing due to higher survival rates of preterm infants and children with multi- organ birth defect syndromes that affect the kidney and urinary tract. We created a mouse model of congenital low nephron number due to deletion of Mta2 in nephron progenitor cells. Mta2 is a core component of the Nucleosome Remodeling and Deacetylase (NuRD) chromatin remodeling complex. These mice developed albuminuria at 4 weeks of age followed by focal segmental glomerulosclerosis (FSGS) at 8 weeks, with progressive kidney injury and fibrosis. Our studies reveal that altered mitochondrial metabolism in the post-natal period leads to accumulation of neutral lipids in glomeruli at 4 weeks of age followed by reduced mitochondrial oxygen consumption. We found that NuRD cooperated with Zbtb7a/7b to regulate a large number of metabolic genes required for fatty acid oxidation and oxidative phosphorylation. Analysis of human kidney tissue also supported a role for reduced mitochondrial lipid metabolism and ZBTB7A/7B in FSGS and CKD. We propose that an inability to meet the physiological and metabolic demands of post-natal somatic growth of the kidney promotes the transition to CKD in the setting of glomerular hypertrophy due to low nephron endowment.

ORGANISM(S): Mus musculus

PROVIDER: GSE246693 | GEO | 2023/11/05

REPOSITORIES: GEO

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Deletion of NuRD component Mta2 in nephron progenitor cells causes developmentally programmed FSGS [E17.RNAseq]

Project description:Low nephron endowment at birth is a risk factor for chronic kidney disease. The prevalence of this condition is increasing due to higher survival rates of preterm infants and children with multi- organ birth defect syndromes that affect the kidney and urinary tract. We created a mouse model of congenital low nephron number due to deletion of Mta2 in nephron progenitor cells. Mta2 is a core component of the Nucleosome Remodeling and Deacetylase (NuRD) chromatin remodeling complex. These mice developed albuminuria at 4 weeks of age followed by focal segmental glomerulosclerosis (FSGS) at 8 weeks, with progressive kidney injury and fibrosis. Our studies reveal that altered mitochondrial metabolism in the post-natal period leads to accumulation of neutral lipids in glomeruli at 4 weeks of age followed by reduced mitochondrial oxygen consumption. We found that NuRD cooperated with Zbtb7a/7b to regulate a large number of metabolic genes required for fatty acid oxidation and oxidative phosphorylation. Analysis of human kidney tissue also supported a role for reduced mitochondrial lipid metabolism and ZBTB7A/7B in FSGS and CKD. We propose that an inability to meet the physiological and metabolic demands of post-natal somatic growth of the kidney promotes the transition to CKD in the setting of glomerular hypertrophy due to low nephron endowment.

2023-11-05 | GSE246694 | GEO

Deletion of NuRD component Mta2 in nephron progenitor cells causes developmentally programmed FSGS [2month.RNAseq]

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Differential gene expression between wild type and Wnt11 mutant embryonic kidneys

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p53 Enables Self Renewal of Nephron Progenitor Cells

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2024-04-08 | PXD043838 | Pride

The long non-coding RNA LINC00941 regulates human epidermal homeostasis through interaction with the MTA2/NuRD complex

Project description:Numerous long non-coding RNAs (lncRNAs) were shown to have functional impact on cellular processes, such as human epidermal homeostasis, but for only a few the mode of action has been elucidated. Here, we report that lncRNA LINC00941 controls keratinocyte differentiation on a global level through association with the MTA2/NuRD complex, one of the major chromatin remodelers in cells. LINC00941 was found to interact with NuRD-associated MTA2, suppressing the expression of the transcription factor EGR3, a regulator of epidermal differentiation. Both, LINC00941 and the MTA2/NuRD complex are enriched in non-differentiated keratinocytes and repress the expression of differentiation genes through epigenetic silencing of EGR3, consequentially repressing premature differentiation of human progenitor cells.

2024-04-08 | GSE237175 | GEO

p53 Enables Self Renewal of Nephron Progenitor Cells

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Transcriptional profiling of human and mouse nephron progenitor cells

Project description:Nephron endowment is determined by the self-renewal and induction of a nephron progenitor pool established at the onset of kidney development. In the mouse, the related transcriptional regulators Six1 and Six2 play non-overlapping roles in nephron progenitors. Transient Six1 activity prefigures, and is essential for, active nephrogenesis. In contrast, Six2 maintains later progenitor self-renewal from the onset of nephrogenesis. We compared Six2’s regulatory actions in mouse and human nephron progenitors by chromatin immunoprecipitation followed by DNA sequencing (ChIP-seq). Surprisingly, SIX1 was identified as a SIX2 target unique to the human nephron progenitors. Further, RNA-seq and immunostaining revealed overlapping SIX1 and SIX2 progenitor activity in the 16 week human fetal kidney. Human SIX1 ChIP-seq revealed a similar set of targets to SIX2, and predicted both factors bind DNA through an identical recognition site. In contrast to the mouse where Six2 binds its own enhancers but doesn’t interact with DNA around Six1, both human SIX1 and SIX2 bind homologous SIX2 enhancers and putative enhancers positioned around SIX1. Transgenic analysis of a putative human SIX1 enhancer in the mouse revealed a transient, mouse-like, pre-nephrogenic, Six1 regulatory pattern. Together, these data demonstrate a divergence in SIX-factor regulation between mouse and human nephron progenitors. In the human, an auto/cross-regulatory loop drives continued SIX1 and SIX2 expression during active nephrogenesis. In contrast, the mouse establishes only an auto-regulatory Six2 loop. It is tempting to speculate that differential SIX-factor regulation may contribute to species differences in the duration of progenitor programs and nephron output.

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