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The Essential Role of ASH2L in Regulating Cell Cycle-Associated Gene Expression to Promote Nephron Progenitor Self-Renewal and Nephron Formation in Mice [RNA-seq]

ABSTRACT: Maintaining adequate nephron number is crucial for normal kidney function, as even slight deficits can predispose individuals to hypertension and other late-onset renal diseases. Congenital anomalies of the kidney and urinary tract arise from abnormal embryonic kidney development, which involves the coordinated reciprocal induction of the ureteric bud and metanephric mesenchyme. Preserving the balance between self-renewal and differentiation of nephron progenitor cells in the metanephric mesenchyme is essential for nephron endowment. Prior work has implicated histone modifications in regulating kidney lineage-specific gene transcription and nephron endowment. Here, we selectively inactivated the H3K4 methyltransferase complex component ASH2L in mouse nephron progenitor cells to elucidate its role in nephron progenitor cell self-renewal and differentiation. The results showed that Ash2l inactivation disrupted H3K4 trimethylation establishment at promoters of genes controlling nephron progenitor cell stemness, differentiation, and cell cycle, leading to premature nephron progenitor cell depletion, cell cycle arrest, and abnormal differentiation of early nephron progenitors, resulting in renal dysplasia at birth. These findings identify ASH2L-mediated H3K4 methylation as a critical epigenetic regulator of kidney development and suggest a novel mechanism contributing to congenital anomalies of the kidney and urinary tract. This knowledge may guide future efforts to unravel the pathogenesis of these conditions and develop targeted therapies.

ORGANISM(S): Mus musculus

PROVIDER: GSE269089 | GEO | 2025/01/09

REPOSITORIES: GEO

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The Essential Role of ASH2L in Regulating Cell Cycle-Associated Gene Expression to Promote Nephron Progenitor Self-Renewal and Nephron Formation in Mice [CUT&TAG]

Project description:Maintaining adequate nephron number is crucial for normal kidney function, as even slight deficits can predispose individuals to hypertension and other late-onset renal diseases. Congenital anomalies of the kidney and urinary tract arise from abnormal embryonic kidney development, which involves the coordinated reciprocal induction of the ureteric bud and metanephric mesenchyme. Preserving the balance between self-renewal and differentiation of nephron progenitor cells in the metanephric mesenchyme is essential for nephron endowment. Prior work has implicated histone modifications in regulating kidney lineage-specific gene transcription and nephron endowment. Here, we selectively inactivated the H3K4 methyltransferase complex component ASH2L in mouse nephron progenitor cells to elucidate its role in nephron progenitor cell self-renewal and differentiation. The results showed that Ash2l inactivation disrupted H3K4 trimethylation establishment at promoters of genes controlling nephron progenitor cell stemness, differentiation, and cell cycle, leading to premature nephron progenitor cell depletion, cell cycle arrest, and abnormal differentiation of early nephron progenitors, resulting in renal dysplasia at birth. These findings identify ASH2L-mediated H3K4 methylation as a critical epigenetic regulator of kidney development and suggest a novel mechanism contributing to congenital anomalies of the kidney and urinary tract. This knowledge may guide future efforts to unravel the pathogenesis of these conditions and develop targeted therapies.

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