Konstantinos Chronis, Ph.D.
Assistant Professor

• BSc(Hons),University of Edinburgh, UK
• MSc by Research(Distinction), University of Edinburgh, UK
• PhD, Kings College London, UK
• Research Fellow: University of California, Los Angeles, CA (Plath lab)

Major Interests:
Cell fate specification is among the most fundamental processes in biology and is exerted physiologically during stem cell differentiation, pathologically during cancer stem cell formation, and can be engineered with reprogramming approaches. All these processes involve activation of target programs and inhibition of donor cell programs and are controlled by sequence-specific DNA binding transcription factors (TFs) and their diverse interactions with the chromatin landscape.

The Chronis Lab aims to understand how TFs decode mammalian genomes to generate the diverse cell identities that arise during development, cellular reprogramming and pathological conditions. To this end we employ multi-omic approaches, genome engineering, single cell tool development and bioinformatic analysis to delineate the TF-driven mechanisms that determine cell fate specification. Our ultimate goal is to engineer customized stem cells and their differentiated progeny for clinical applications while exploring the mechanisms that govern organ regeneration and tumor growth.

A Multi-Scale Analysis of Cell fate Commitment and Reprogramming

How are pluripotent Stem Cells “programmed” to generate all bodily cell types during development, and how can somatic cells be “reprogrammed” to an ESC-like state? To delineate the events that drive cell fate decisions we use genomic and single cell approaches to identify markers and cell type specific signatures that can distinguish cell states and the regulatory mechanisms that govern the production of such diversity (Chronis&Fiziev et al Cell 2017; Pasque&Karnik& Chronis Stem Cell Reports, 2018, Sridharan et al Nature Cell Biology 2013). By applying innovative technologies, we create detailed atlases of regulatory DNA and characterize novel chromatin states and their function in the establishment and maintenance of cell identity. We aim to understand the impact of chromatin reprogramming on cell fate commitment in normal development and during initiation and cancer progression.

Mechanism of Transcription factor assembly and binding dynamics in gene regulation  

Activation and repression of developmental gene expression programs are controlled by the combinatorial actions of sequence specific transcription factors (TFs) and their effects on 3D genome organization (Denholtz et al Cell Stem Cell, 2013; Zhang& Chronis Cell Stem Cell 2019). Yet, how TFs identify and select their genomic targets from thousands of potential binding sites remains unclear. We are assessing the contribution of DNA sequence variation, chromatin content, RNA presence and modalities of TF interactions on genomic target selection. Current research in the lab is aimed at understanding how reprogramming transcription factors facilitate the loss or destabilization of somatic cell identities by repressing diverse somatic gene regulatory programs and how these pathways potentially contribute to malignancies that involve de-differentiation of somatic tissues.

Engineering customized Hematopoietic Stem, Progenitor and Mature Blood cells

Hematopoietic Stem Cells (HSCs) represent a rare cell type capable of reconstituting all blood lineages, and through transplantation the only curative therapy for the treatment of blood disorders. In vitro generation of clinically relevant blood progenitors holds great promise for regenerative medicine and makes disease modeling, toxicity screening, and immunotherapy tangible. Significant challenges in HSC expansion and failure to differentiate HSCs from pluripotent stem cells in vitro, makes direct conversion of somatic cells to HSCs (iHSCs) and/or their differentiated descendants into an attractive approach. We use novel computational and systems biology approaches to define and manipulate key cis regulatory elements that contribute to HSC specification and the factors that contribute to differentiation towards lymphoid lineages.

Novel tools to study Epigenetic regulation, Chromatin architecture, and TF dynamics

 While traditional transcriptomic, epigenetic, and proteomic profiling methods have provided key insights in gene regulation, chromatin structure and protein function they typically rely on large populations of cells, are largely correlative, and fail to capture dynamic transitions in a direct manner. We are developing novel co-assays that measure protein binding and transcriptional output within single cells of heterogeneous populations to measure in a quantitative manner the causal relationships between transcription factor binding and gene regulation.

Selected publications:

Pandya-Jones A, Markaki Y, Serizay J, Chitiashvili T, Mancia Leon WR, Damianov A, Chronis C, Papp B, Chen CK, McKee R, Wang XJ, Chau A, Sabri S, Leonhardt H, Zheng S, Guttman M, Black DL, Plath K. A protein assembly mediates Xist localization and gene silencing.  Nature. 2020 Nov;587(7832):145-151.

Zhang W*, Chronis C*, Chen X, Zhang H, Spalinskas R, Pardo M, Chen L, Wu G, Zhu Z, Yu Y, Yu L, Choudhary J, Nichols J, Parast MM, Greber B, Sahlén P, Plath K. The BAF and PRC2 Complex Subunits Dpf2 and Eed Antagonistically Converge on Tbx3 to Control ESC Differentiation. Cell Stem Cell. 2019 Jan 3;24(1):138-152.e8

Pasque V*, Karnik R*, Chronis C*, Petrella P, Langerman J, Bonora G, Song J, Vanheer L, Sadhu Dimashkie A, Meissner A, Plath K. X Chromosome Dosage Influences DNA Methylation Dynamics during Reprogramming to Mouse iPSCs. Stem Cell Reports. 2018 May 8;10(5):1537-1550. 

Chronis C*, Fiziev P*, Papp B, Butz S, Bonora G, Sabri S, Ernst J, Plath K. Cooperative Binding of Transcription Factors Orchestrates Reprogramming. Cell. 2017 Jan 26;168(3):442-459.e20

Denholtz M*, Bonora G*, Chronis C, Splinter E, de Laat W, Ernst J, Pellegrini M, Plath K. Long-range chromatin contacts in embryonic stem cells reveal a role for pluripotency factors and polycomb proteins in genome organization. Cell Stem Cell. 2013 Nov 7;13(5):602-16

Sridharan R, Gonzales-Cope M*, Chronis C*, Bonora G, McKee R, Huang C, Patel S, Lopez D, Mishra N, Pellegrini M, Carey M, Garcia BA, Plath K. Proteomic and genomic approaches reveal critical functions of H3K9 methylation and heterochromatin protein-1γ in reprogramming to pluripotency. Nat Cell Biol. 2013 Jul;15(7):872-82