RESEARCH OVERVIEW
We are interested in understanding how chromatin-based regulatory pathways control genome function, with our current research centered on three interconnected areas:
(i) Dissecting how combinatorial histone modifications regulate the recruitment and activity of chromatin-associated proteins
(i) Investigating the molecular mechanisms underlying lifelong reorganization of the epigenetic landscape in mammals, and
(ii) Developing mass spectrometry-based approaches for quantitative analysis of chromatin proteins and histone post-translational modifications at subnuclear and single-cell resolution.
Advancing Chromatin Research with Cutting-Edge Proteomics
In eukaryotic cells, nuclear DNA is organized together with histone proteins and other factors into chromatin — a highly complex and dynamic structure that controls genome function. Chromatin carries a diverse array of covalent modifications that regulate the recruitment and activity of molecular machinery involved in transcriptional activation and repression, DNA repair, and replication. Most modifications cluster on histones, forming complex patterns that provide the basis for the so-called regulatory 'histone code.' Unlike the static genetic code, histone modifications are dynamic, enabling genome organization and gene transcription to adapt to cellular needs. This plasticity is crucial for many processes, including development and the timely response to internal and external stimuli, while disruptions in modification pathways are linked to diseases and age-related functional decline. Despite extensive research on individual modifications, how their complex and interconnected patterns regulate genome organization and function remains largely unclear (Fig. 1).
Figure 1: Chromatin organization and function are shaped by combinatorial patterns of histone modifications and the nuclear proteins that recognize and respond to them. Our lab develops and applies advanced proteomic approaches to systematically characterize these regulatory components and uncover how they work together to control genome function.
Our research, along with findings from others, has revealed that modifications often function collaboratively, with many capable of modulating the placement, removal, and downstream effects of others. Furthermore, the binding of many critical regulatory factors - such as transcriptional activators, repressors, and chromatin remodelers - is often regulated by multiple co-existing modifications present on the same nucleosome (read more). To understand how complex modification landscapes regulate genome function, it is therefore critically important to comprehensively investigate both the full spectrum of histone modifications and the nuclear proteins that act together to shape specific regulatory outcomes. This poses a significant technical challenge, as most current techniques, like chromatin immunoprecipitation followed by sequencing (ChIP-seq), are limited to a narrow range of target modifications and proteins, restricting their ability to capture the full complexity of chromatin regulatory circuits. To overcome these limitations, we are developing advanced mass spectrometry-based proteomics methods for the comprehensive, quantitative profiling of chromatin-associated proteins and histone modifications across distinct nuclear territories and at single-cell resolution. Combined with next-generation sequencing, these approaches offer a deep molecular view of distinct chromatin domains, enabling us to examine their dynamic remodeling across processes like aging, cellular differentiation, and reprogramming. Drawing on our expertise in proteomics and recent advances in mass spectrometry, we aim to establish integrative multi-omics pipelines designed to provide critical insights into chromatin regulation in health and disease.
Decoding Lifelong Epigenetic Trajectories to Combat Aging
Epigenetic information, encoded in complex modification patterns on DNA and histone proteins, enables eukaryotic cells to differentially utilize the same genome, allowing them to perform specialized functions required for the formation of complex multicellular life forms. Mammalian organisms are composed of hundreds of distinct cell types, most of which acquire their unique epigenetic makeup during early development. Various molecular pathways then ensure that the cell-type-specific epigenomes are maintained over time to preserve cell identity and functions.
Paradoxically, we and others have shown that the epigenetic landscapes of mammalian cells are not static but progressively change in a non-random manner throughout life (Fig. 2; see our work for more on histone modification changes, and studies by others on DNA methylation changes). Although the full extent of age-related epigenetic reorganization remains to be elucidated, many aberrations observed in aged cells, such as heterochromatin loss, have been directly linked to genomic dysfunctions and are considered as key drivers of age-associated physiological decline and disorders.
Figure 2: A schematic inspired by Waddington's epigenetic landscape, illustrating the concept that the cellular epigenome undergoes progressive, non-random changes throughout life, which ultimately contribute to genome misregulation.
Strikingly, emerging data suggest that at least some age-related epigenetic aberrations can be reversed, offering the potential to restore key physiological functions. However, despite this great promise, our understanding of the intricate relationship between epigenetics and aging remains in its infancy. While most research has centered on age-associated changes in DNA methylation, much less is known about how other epigenetic layers - such as distinct histone modifications and non-canonical histone variants - change throughout the lifespan. It also remains unclear what drives the reorganization of the epigenetic modification landscape and how these changes affect chromatin organization and genome function. Answering these questions is essential for understanding the molecular basis of age-associated physiological decline and pathologies, and may help inform therapeutic strategies to preserve cellular function and ultimately extend healthy lifespan.
Our scientific mission is to provide a systematic comprehensive characterization of how chromatin modification and protein landscapes change over the course of life. By integrating unbiased quantitative proteomics with genomics approaches we aim to capture the full scope and spatiotemporal dynamics of age-related epigenetic alterations across different tissues and cell types. By combining this data with functional biochemical assays, gene editing tools, and various cellular models, we aspire to dissect the molecular mechanisms underlying genome dysfunction in aged cells and uncover key pathways that drive age-associated epigenetic decline and disease.