Project Grant R21AI180563

THE BTB-ZF TRANSCRIPTION FACTOR, PLZF, REQUIRES YY1 TO FUNCTION - MULTIPLE BTB-ZF FAMILY TRANSCRIPTION FACTORS ARE ESSENTIAL FOR IMMUNE SYSTEM DEVELOPMENT AND/OR ESSENTIAL IMMUNE SYSTEM FUNCTIONS. SOME BTB-ZF TRANSCRIPTION FACTORS FUNCTION, ESSENTIALLY, AS "TOGGLE SWITCHES" THAT CONTROL KEY DECISION POINTS DURING DEVELOPMENT. FOR EXAMPLE, THE COMMITMENT OF LYMPHOCYTES INTO THE T OR B CELL LINEAGE REQUIRES LRF AND COMMITMENT TO THE CD4 OR CD8 T CELL LINEAGE REQUIRES THPOK. LOSS OF EXPRESSION OF THE NECESSARY BTB-ZF GENE RESULTS IN LOSS OF CELL LINEAGE IDENTIFY AND DEDIFFERENTIATION. OTHER BTB-ZF FAMILY MEMBERS CONTROL ESSENTIAL OR UNIQUE EFFECTOR FUNCTIONS OF LYMPHOCYTES. ZBTB20, FOR EXAMPLE, DEFINES THE FUNCTION OF NATURAL IL-10 PRODUCING TREGS THAT ARE NECESSARY FOR INTESTINAL HOMEOSTASIS. BCL6 IS REQUIRED FOR BOTH THE DEVELOPMENT OF T FOLLICULAR HELPER CELLS AND GERMINAL CENTER B CELLS AND ZBTB32 IS REQUIRED FOR THE PROLIFERATIVE BURST OF NK CELLS IN RESPONSE TO VIRUSES. IN THIS APPLICATION, WE SHOW THAT THE FUNCTION OF PLZF, THE BTB-ZF TRANSCRIPTION THAT CONTROLS THE PHENOTYPE AND INNATE LIKE EFFECTOR FUNCTIONS OF INVARIANT NATURAL KILLER (NKT) CELLS, REQUIRES YIN YANG 1 (YY1). YY1 IS A MULTI-FACETED TRANSCRIPTIONAL REGULATOR THAT BELONGS TO THE POLYCOMB PROTEIN FAMILY. YY1 IS UBIQUITOUSLY EXPRESSED AND IS IMPORTANT FOR MULTIPLE, DIVERSE BIOLOGICAL PROCESSES. YY1 FUNCTIONS TO REGULATE GENE TRANSCRIPTION DIRECTLY, VIA CHROMATIN MODIFICATIONS, VIA DIRECT INTERACTIONS WITH OTHER TRANSCRIPTION FACTORS AND EVEN BY IMPACTING HIGHER ORDER FUNCTIONS SUCH AS BY 3D CHROMATIN LOOPING OR PHASE SEPARATION. THE GOAL OF THIS APPLICATION IS TO DISCRIMINATE BETWEEN DIFFERENT POSSIBLE MECHANISMS BY WHICH YY1 CONTROLS PLZF. IN DOING SO, WE ANTICIPATE THAT WE WILL SIGNIFICANTLY ADVANCE THE UNDERSTANDING OF THE REGULATION OF BTB- ZF MASTER REGULATOR TRANSCRIPTION FACTORS. WE ANTICIPATE THAT WE WILL ALSO LEARN MORE ABOUT HOW THE UBIQUITOUSLY EXPRESSED, MULTI-FACETED TRANSCRIPTION REGULATOR YY1 CONTROLS DISCRETE BIOLOGICAL FUNCTIONS IN DIFFERENT CELL TYPES. ADVANCES IN THESE AREAS WOULD FILL SUBSTANTIAL KNOWLEDGE GAPS AND HAVE THE POTENTIAL TO IMPACT BOTH THE UNDERSTANDING OF IMMUNE RESPONSES AND, MOST LIKELY, OTHER BIOLOGICAL SYSTEMS WHERE BTB-ZF GENES PLAY IMPORTANT ROLES. OVERALL, OUR APPLICATION SEEKS TO UNDERSTAND HOW A LINEAGE SPECIFIC TRANSCRIPTION FACTOR (PLZF) IS CONTROLLED BY A UBIQUITOUSLY EXPRESSED CO-FACTOR (YY1) RESULTING IN LYMPHOCYTE SUBSET DISCRETE EFFECTOR FUNCTIONS.