Telomere position effect: regulation of gene expression with progressive telomere shortening over long distances.
While global chromatin conformation studies are emerging, very little is known about the chromatin conformation of human telomeres. Most studies have focused on the role of telomeres as a tumor suppressor mechanism. Here we describe how telomere length regulates gene expression long before telomeres become short enough to produce a DNA damage response (senescence). We directly mapped the interactions adjacent to specific telomere ends using a Hi-C (chromosome capture followed by high-throughput sequencing) technique modified to enrich for specific genomic regions. We demonstrate that chromosome looping brings the telomere close to genes up to 10 Mb away from the telomere when telomeres are long and that the same loci become separated when telomeres are short. Furthermore, expression array analysis reveals that many loci, including noncoding RNAs, may be regulated by telomere length. We report three genes (ISG15 [interferon-stimulated gene 15 kd], DSP [Desmoplakin], and C1S [complement component 1s subcomplement]) located at three different subtelomeric ends (1p, 6p, and 12p) whose expressions are altered with telomere length. Additionally, we confirmed by in situ analysis (3D-FISH [three-dimensional fluorescence in situ hybridization]) that chromosomal looping occurs between the loci of those genes and their respective telomere ends. We term this process TPE-OLD for "telomere position effect over long distances." Our results suggest a potential novel mechanism for how telomere shortening could contribute to aging and disease initiation/progression in human cells long before the induction of a critical DNA damage response.
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
Jérôme D
JD
Robin
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
Andrew T
AT
Ludlow
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
Kimberly
K
Batten
UMRS 910, INSERM, Aix Marseille University, Marseille 13385 Cedex 05 France;
Frédérique
F
Magdinier
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
Guido
G
Stadler
Center for Genetic Muscle Disorders, Kennedy Krieger Institute, Baltimore, Maryland 21205, USA; Department of Neurology, Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, USA;
Kathyrin R
KR
Wagner
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA; Center for Excellence in Genomics Medicine Research, King Abdulaziz University, Jeddah 21589, Saudi Arabia jerry.shay@utsouthwestern.edu.
Jerry W
JW
Shay
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
Woodring E
WE
Wright
D002478:Cells, Cultured; D002843:Chromatin / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D032446:Myoblasts / Q000166:cytology; D016615:Telomere / Q000235:genetics* / Q000378:metabolism*; D059506:Telomere Shortening / Q000235:genetics*
D002843:Chromatin
age-dependent gene expression; cancer; chromatin; chromosome looping; replicative aging; senescence; telomerase