Clonal Hematopoiesis of Indeterminate Potential and DNA Methylation in Aging and Disease

Explore clonal hematopoiesis of indeterminate potential (CHIP) and DNA methylation in aging and disease through this comprehensive lecture from the Computational Genomics Summer Institute. Delve into the role of DNA methylation in gene regulation and cell fate determination, and learn about the detection and implications of clonal hematopoiesis. Examine the association between CHIP and increased disease risk, and investigate the underlying mechanisms using TOPMed whole genome sequencing data. Gain insights into epigenome-wide association studies (EWAS), including examples related to aging and clonal hematopoiesis. Discover how cell type proportions are estimated from DNA methylation data, with a focus on reference-based approaches for blood samples. Analyze DNMT3A and TET2 EWAS profiles and their significance in understanding CHIP. Explore the relationship between CHIP-associated CpGs and chromatin accessibility, as well as enrichment for hematopoietic stem cell gene expression signatures. Conclude by examining how CHIP mutations lead to clonality and discussing the broader implications for aging and disease.

Syllabus

Intro
Role of DNAm in gene regulation
Role of DNAm in cell fate determination
Detection of clonal hematopoiesis
CHIP associates with increased disease risk
Clonal hematopoiesis: much remains unknown about underlying mechanisms
Background: TOPMed WGS data
Discovery and replication samples
Epigenome-wide association studies (EWAS)
Example EWAS: DNAm in aging
EWAS for clonal hematopoiesis
Cell type proportions estimated from DNAM data
Reference-based approaches often used with blood
DNMT3A and TET2 EWAS profiles: what do they tell us?
Are CHIP-associated CpGs in regions of chromatin accessibility?
Enrichment for HSC gene expression signatures
Conclusions: How do CHIP mutations lead to clonality?