講演要旨

It is established that swift migration through tight interstitial tissue spaces by an armamentarium of cell
types is conducted by malleable nuclear structures. However, molecular programs that instruct nuclear
shapes remain to be revealed. Here I will present our recent observations indicate that loss of loop
extrusion rapidly converts macrophage/granulocyte progenitors into cells that display a myriad of nuclear
shapes, including horse-shoe, ring and hyper-segmented nuclear morphologies. The conversion of
mononuclear to polymorphonuclear cells was accompanied by massive chromatin remodeling at
enhancers that harbored cis-elements associated with neutrophil-specific transcription factors. Halting
loop extrusion acutely activated the expression of genes encoding for factors that instruct neutrophil
development, activation, migration, extravascular migration, inflammation and respiratory bursts to
neutralize phagocytosed bacteria. Additionally, cessation of loop extrusion in bone marrow
hematopoietic progenitors enriched for cells that express a macrophage transcription signature. These
data indicate that loop extrusion programs regulate nuclear shape and that halting loop extrusion acutely
activates a neutrophil specific gene program. We propose that modulating loop extrusion programs
facilitates the migration of cells through densely populated tissues by instructing the assembly of distinct
nuclear shapes whereas aberrant loop extrusion programs instruct alterations in nuclear morphologies to
promote metastatic cell migration, aging, cardiovascular disease and beyond.

Flyer (Prof. Murre)