Symposium 11 - Epigenetic and Disease

Epigenetics is a fascinating field of biology that explores how external factors can influence gene expression without altering the underlying DNA sequence. This intricate regulatory system plays a crucial role in determining how genes are turned on or off, impacting everything from physical traits to susceptibility to diseases. This talk will provide an overview of the concept of epigenetics, explaining how environmental factors, lifestyle choices, and even experiences can lead to epigenetic changes that affect our health.


Understanding epigenetics is particularly relevant in the context of diseases such as cancer and developmental disorders. Many cancers and developmental diseases arise not solely from genetic mutations; rather, epigenetic modifications can also drive the development and progression of tumors and influence normal development. By examining how these changes occur, researchers are uncovering new insights into cancer biology and developmental processes, which can lead to innovative approaches for prevention, diagnosis, and treatment.


Moreover, epigenetics offers answers to longstanding questions about the heritability of traits and diseases. It provides a framework for understanding how certain conditions can be passed down through generations, not just through DNA, but also through epigenetic markers that can influence gene expression in offspring.


This presentation will delve into the mechanisms of epigenetic regulation, explore its implications for health and disease, and discuss the potential for epigenetic therapies. Bridging the gap between complex scientific concepts and everyday understanding highlights the significance of epigenetics in contemporary health and medicine, emphasizing its transformative potential in the approach to disease and human biology. Join in the exploration of the mysteries of epigenetics and its profound impact on the understanding of health and disease.

While the genome serves as the instruction manual encoding all biological functions in our cells, the epigenome provides the annotations and footnotes that dictate how our DNA is correctly interpreted. Cellular functions require appropriate transcriptional activation and repression through chemical modifications on DNA and their associated histone proteins. These epigenetic marks modulate various non-coding sequences to establish cell-type specific transcriptional programs. Our research investigates how these molecular mechanisms govern gene expression in development and disease, focusing specifically on repetitive elements and cis-regulatory elements, which comprise roughly half the human genome. These sequences play crucial roles in modulating gene expression. This presentation will detail how such elements influence the epigenome and higher-order chromatin structure in mammalian cells. Through a multi-faceted approach combining epigenomic assays, genome engineering, and cellular and molecular biology techniques, we have identified specific elements that function as regulators of important genes in complex human pathologies. These sequences can affect the recruitment of specific transcription factors, chromatin modifiers, or alter 3D chromatin architecture. Understanding these intricate processes is essential for deciphering the functional roles of repetitive elements in both normal physiology and disease pathogenesis, ultimately paving the way for novel therapeutic interventions targeting epigenetic dysregulation.

Lynch syndrome results from germline mutations in DNA mismatch repair genes (MSH2, MLH1, MSH6, PMS2) or epigenetic MSH2 inactivation via EPCAM deletion. Epigenetic MLH1 promoter methylation, the main cause of sporadic colorectal cancer with microsatellite instability, has unclear mechanisms. BRAF V600E mutations often precede MLH1 loss in serrated polyps. In most MLH1-deficient sporadic cancers, methylation is limited to tumour tissue, but constitutional MLH1 epimutation, found in normal tissues, increases cancer risk similar to Lynch syndrome, with early-onset colorectal/endometrial cancers and frequent metachronous tumours. These cases lack germline MLH1 mutations and somatic BRAF V600E, showing second MLH1 allele inactivation in tumours. Unlike Lynch syndrome, most epimutation patients lack a strong family cancer history. Inheritance varies: rare inconsistent transmission, autosomal dominant patterns, or common de novo cases without offspring transmission. Given the variable inheritance risks, patients with early-onset MLH1-deficient cancers require referral for genetic diagnosis and comprehensive counseling. Genetic workup should include promoter methylation analysis, particularly when no germline MLH1 mutation is identified.