Biophysical Society Thematic Meeting

Biophysics in the Understanding, Diagnosis, and Treatment of Infectious Diseases Poster Abstracts

15-POS

Board 15

The UMLILO Long ncRNA Exploits Pre-formed 3D Chromatin Folding to Coordinate

Rapid Chemokine Gene Activation

Stephanie Fanucchi

1,2

, Ezio T. Fok

1,2

, Emiliano Dalla

, Youtaro Shibayama

1,2

, Stoyan

Stoychev

, Maxim Imakaev

, Ken W. Sung

, Musa M. Mhlanga

1,2,7

Gene Expression and Biophysics Group, BTRI, CSIR Biosciences, Pretoria, South

Africa,

Division of Chemical, Systems & Synthetic Biology, Faculty of Health Sciences, Cape

Town, South Africa,

Functional Genomics and Bioinformatics Unit, Lab. Naz. Consorzio

Interuniversitario Biotecnologie, Trieste, Italy,

Biomedical Technologies Group, CSIR

Biosciences, Pretoria, South Africa,

Harvard-MIT Division of Health Sciences and Technology,

Massachusetts Institute of Technology, Boston, MA, USA,

School of Computing, National

University of Singapore, Genome Institute of Singapore, Genome Institute of Singapore,

Singapore,

Gene Expression and Biophysics Unit, Instituto de Medicina Molecular, Lisbon,

Portugal.

Long non coding RNAs (LncRNAs) are emerging as key intermediates that control gene

regulation by coordinating 3D chromatin structure. Here we report a new super-enhancer

resident enhancer-like lncRNA, UMLILO, which is brought in close proximity to the chemokine

genes by pre-formed chromosomal contacts. Despite lacking a homolog in mice, we show that

depletion of UMLILO by siRNA or CRISPR-mediated replacement with an EGFP reporter is

sufficient to abrogate chemokine transcription in human cells. By acting in cis, UMLILO uses

the local 3D chromatin compaction of the pre-formed chemokine TAD to direct the WDR5-

MLL1 complex across the chemokine promoters, facilitating their H3K4me3 activation. In this

way, we reveal how pre-formed chromatin loop organization can act as a topological platform to

insulate a key transcriptional pathway from gene-intrinsic noise, to achieve rapid and robust

chemokine expression. Remarkably, by replacing UMLILO with HOTTIP at its endogenous

genomic location, we show the activity of UMLILO can be substituted with a different WDR5-

interacting lncRNA. As aberrant expression of these chemokines underlies multiple disease

states, such as severe sepsis, adjustment of chemokine levels by altering UMLILO activity may

represent a valuable therapeutic strategy.