[초청강연] Unraveling long noncoding RNA function in the 3D genome

Unraveling long noncoding RNA function in the 3D genome

Hyun Jung Oh
Massachusetts General Hospital, Harvard Medical School

The mammalian genome is spatially organized at multiple levels. How a chromosome is folded
into loops in the 3D genome is closely linked to dynamic regulation of gene expression.
Therefore, chromosome loops form and change dynamically during development, homeostasis,
and disease. Here we have revealed the long noncoding RNA Jpx as the first RNA that
modulates the chromosome looping landscape on a genome-wide scale, thereby controlling gene
expression. Noncoding RNAs have been appreciated as the hidden mechanisms underlying
complex gene regulation in mammals. While protein-coding genes account for only ~2% of the
entire genome, the majority of the genome is pervasively transcribed, producing noncoding
RNAs. Long noncoding RNAs have emerged as critical regulators involved in diverse
physiological and pathological contexts. By mapping Jpx binding sites across the genome, we
have found that Jpx RNA binds thousands of genomic sites and preferentially occupies the
promoters of active genes during differentiation of mouse embryonic stem cells. Strikingly,
depleting Jpx RNA causes a massive shift in the formation of chromosome loops — thousands
of new loops arise, replacing original loops. At mechanistic level, Jpx selectively controls a

subset of CTCF, an architectural protein that anchors the loops. Jpx specifically regulates low-
affinity, developmentally sensitive CTCF sites, where it competitively displaces CTCF from

DNA. When Jpx is ablated in cells, CTCF binds ectopically to the low-affinity sites, which
serve as anchors of new loops. This results in a “shifting” of the loop anchor to a new site and
explains the displacement of thousands of chromosome loops in the absence of Jpx RNA. Our
study demonstrates that Jpx RNA controls the global patterns of CTCF binding by operating as a
CTCF release factor and, in this way, determines anchor site usage in dynamic organization of
3D genome. This finding provides a basis for exploring other transcripts in 3D genome
regulation and has implications for how dysregulation of noncoding RNAs and aberrant loop
formation lead to pathological consequences.