TY - JOUR
T1 - Functional characterization of enhancer activity during a long terminal repeat's evolution
AU - Du, Alan Y.
AU - Zhuo, Xiaoyu
AU - Sundaram, Vasavi
AU - Jensen, Nicholas O.
AU - Chaudhari, Hemangi G.
AU - Saccone, Nancy L.
AU - Cohen, Barak A.
AU - Wang, Ting
N1 - Funding Information:
We thank J. Hoisington-López and M.L. Jaeger from The Edison Family Center for Genome Sciences & Systems Biology (CGSSB) for assistance with sequencing. This work was funded by National Institutes of Health grant numbers R01HG007175, U01 CA200060, U01HG009391, U41HG010972, and U24HG012070. A.Y.D. was supported by National Human Genome Research Institute training grant T32 HG000045.
Publisher Copyright:
© 2022 Du et al.
PY - 2022/10
Y1 - 2022/10
N2 - Many transposable elements (TEs) contain transcription factor binding sites and are implicated as potential regulatory elements. However, TEs are rarely functionally tested for regulatory activity, which in turn limits our understanding of how TE regulatory activity has evolved.We systematically tested the human LTR18A subfamily for regulatory activity using massively parallel reporter assay (MPRA) and found AP-1- and CEBP-related binding motifs as drivers of enhancer activity. Functional analysis of evolutionarily reconstructed ancestral sequences revealed that LTR18A elements have generally lost regulatory activity over time through sequence changes, with the largest effects occurring owing to mutations in the AP-1 and CEBP motifs. We observed that the two motifs are conserved at higher rates than expected based on neutral evolution. Finally, we identified LTR18A elements as potential enhancers in the human genome, primarily in epithelial cells. Together, our results provide a model for the origin, evolution, and co-option of TE-derived regulatory elements.
AB - Many transposable elements (TEs) contain transcription factor binding sites and are implicated as potential regulatory elements. However, TEs are rarely functionally tested for regulatory activity, which in turn limits our understanding of how TE regulatory activity has evolved.We systematically tested the human LTR18A subfamily for regulatory activity using massively parallel reporter assay (MPRA) and found AP-1- and CEBP-related binding motifs as drivers of enhancer activity. Functional analysis of evolutionarily reconstructed ancestral sequences revealed that LTR18A elements have generally lost regulatory activity over time through sequence changes, with the largest effects occurring owing to mutations in the AP-1 and CEBP motifs. We observed that the two motifs are conserved at higher rates than expected based on neutral evolution. Finally, we identified LTR18A elements as potential enhancers in the human genome, primarily in epithelial cells. Together, our results provide a model for the origin, evolution, and co-option of TE-derived regulatory elements.
UR - http://www.scopus.com/inward/record.url?scp=85141889159&partnerID=8YFLogxK
U2 - 10.1101/gr.276863.122
DO - 10.1101/gr.276863.122
M3 - Article
C2 - 36192170
AN - SCOPUS:85141889159
SN - 1088-9051
VL - 32
SP - 1840
EP - 1851
JO - Genome research
JF - Genome research
IS - 10
ER -