Georgopoulos Lab

Overview

We study how lineage identity is established and maintained in hematopoietic and immune systems, focusing on the IKAROS family of transcription factors and associated chromatin remodeling complexes. We have established IKAROS as a foundational regulator of lymphocyte development, acting from hematopoietic stem cells to mature T and B cell effector states by organizing epigenetic landscapes and transcriptional networks that encode cell fate decisions. Disruption of IKAROS activity drives immunodeficiency, leukemias, autoimmunity and inflammatory disease.

Research Projects

Through the following projects we investigate how lineage identity is encoded, stabilized, and executed through chromatin architecture

Project 1: Encoding Lineage Bias at the Root of the Hematopoietic System Through Chromatin Architecture

We investigate how chromatin regulatory architecture encodes lineage bias in hematopoietic stem and progenitor cells (HSPCs) prior to overt transcriptional commitment. Our work identified the Ikaros gene family and established IKAROS as a pioneering transcription factor that regulates lymphoid lineage potential at earliest stages of hematopoiesis. Our genetic ablation studies demonstrated that loss of IKAROS results in developmental arrest prior to the emergence of lymphoid-restricted progenitors.

Building on these findings, we examine how lineage priming is initiated within HSPCs and how early epigenetic regulation balances multipotency and lineage restriction. We defined the lymphoid-primed multipotent progenitor (LMPP) as a key branch point in hematopoiesis and showed that lymphoid priming is mediated by IKAROS. Together with the identification of antagonistic interactions between IKAROS and the chromatin remodeler Mi-2β (CHD4), these studies established epigenetic control as central to early lineage decisions.

Our current studies focus on the coordination of enhancer accessibility, transcription factor networks, and regulatory element connectivity across the early hematopoietic hierarchy. We are particularly interested in how IKAROS integrates these regulatory layers to establish lineage bias while restricting aberrant lineage programs.

Using single-cell multiomic approaches, we seek to define the fundamental principles by which these enhancer networks are initially established in a multipotent context and subsequently resolved into lineage-specific programs, and how IKAROS coordinates this process to promote lymphoid fate while restricting aberrant myeloid skewing.

We seek to define how enhancer landscapes are organized into HSC-centered regulatory networks that progressively resolve into lineage-specific trajectories. These studies establish that lineage bias is embedded within chromatin architecture early in hematopoiesis.

Together, this work defines a framework in which lineage fate is encoded at the level of chromatin organization, linking early regulatory architecture in stem cells to downstream differentiation outcomes and disease.

Project 2: Chromatin regulation of Lymphocyte Function

We investigate how chromatin architecture and transcription factor networks control lymphocyte function. Our goal is to define how IKAROS shapes chromatin architecture in developing and mature lymphocytes to enable appropriate immune response and maintain long-term immune cell homeostasis.

Our work has established that IKAROS regulates lymphocyte development and function across increasing levels of regulatory complexity from DNA binding to recruitment of chromatin remodeling complexes to modulating chromatin access of super-enhancers that governs lineage-specific gene expression in differentiating B cell precursors. We have shown that IKAROS controls thresholds for T and B cell activation, and we are now investigating how these thresholds are encoded at the level of chromatin-based regulatory states.

Our studies focus on the coordination of chromatin access to enhancer networks for transcription factor circuits and their long-range chromatin communications,during lymphocyte activation. We are particularly interested in how IKAROS establishes and maintains these regulatory structures, and how their disruption rewires cellular identity to promote aberrant immune responses and altered intercellular communication, including B–T cell interactions.
Using integrated genomic, single-cell, and 3D genome approaches including reversible IKAROS perturbation, we define how chromatin architecture and genome organization regulate transcription factor engagement during both early differentiation and effector function. These studies extend to patient-derived systems, to examine how changes in chromatin architecture contribute to leukemia and immune-mediated disease.

Together, this work defines a framework in which IKAROS integrates transcriptional control, chromatin remodeling, and genome organization to regulate lymphocyte function and maintain immune cell homeostasis.