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DNMT3A haploinsufficiency causes dichotomous DNA methylation defects at enhancers in mature human immune cells

ABSTRACT: DNMT3A haploinsufficiency causes dichotomous DNA methylation defects at enhancers in mature human immune cells

PROVIDER: PRJNA713766 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13938300_1.fastq.gz	Fastqsanger.gz
	SRR13938300_2.fastq.gz	Fastqsanger.gz
	SRR13938301_1.fastq.gz	Fastqsanger.gz
	SRR13938301_2.fastq.gz	Fastqsanger.gz
	SRR13938302_1.fastq.gz	Fastqsanger.gz

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DNMT3A haploinsufficiency causes dichotomous DNA methylation defects at enhancers in mature human immune cells [tiling array]

Project description:DNMT3A encodes an enzyme that carries out de novo DNA methylation, which is essential for the acquisition of cellular identity and specialized functions during cellular differentiation. It is the most common driver gene of age-related clonal hematopoiesis. As such, mature immune cells harboring DNMT3A mutations can be readily detected in elderly individuals. Most acquired DNMT3A mutations are heterozygous and predicted to cause loss-of-function, indicating that haploinsufficiency is the predominant pathogenic mechanism. Yet, whether and how DNMT3A haploinsufficiency affects the function of mature immune cells is poorly understood. Here, we demonstrate that DNMT3A haploinsufficiency impairs the gain of DNA methylation at decommissioned enhancers, while simultaneously and unexpectedly impairs DNA demethylation at thousands of newly activated enhancers in mature human myeloid cells. The DNA methylation defects alter the activity of affected enhancers, leading to abnormal gene expression and impaired immune response. These findings provide insights into the mechanism of immune dysfunction associated with acquired DNMT3A mutations and clonal hematopoiesis.

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DNMT3A haploinsufficiency causes dichotomous DNA methylation defects at enhancers in mature human immune cells.

Project description:DNMT3A encodes an enzyme that carries out de novo DNA methylation, which is essential for the acquisition of cellular identity and specialized functions during cellular differentiation. DNMT3A is the most frequently mutated gene in age-related clonal hematopoiesis. As such, mature immune cells harboring DNMT3A mutations can be readily detected in elderly persons. Most DNMT3A mutations associated with clonal hematopoiesis are heterozygous and predicted to cause loss of function, indicating that haploinsufficiency is the predominant pathogenic mechanism. Yet, the impact of DNMT3A haploinsufficiency on the function of mature immune cells is poorly understood. Here, we demonstrate that DNMT3A haploinsufficiency impairs the gain of DNA methylation at decommissioned enhancers, while simultaneously and unexpectedly impairing DNA demethylation of newly activated enhancers in mature human myeloid cells. The DNA methylation defects alter the activity of affected enhancers, leading to abnormal gene expression and impaired immune response. These findings provide insights into the mechanism of immune dysfunction associated with clonal hematopoiesis and acquired DNMT3A mutations.

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DNMT3A haploinsufficiency causes dichotomous DNA methylation defects at enhancers in mature human immune cells

Project description:This SuperSeries is composed of the SubSeries listed below.

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