Investigating the role of CCCTC-binding factor in osteoarthritis pathogenesis

Hijazi, Alaa

doi:10.1016/j.joca.2018.02.332

Cited by 1 publication

(1 citation statement)

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“…For example, predicted motifs for KLF5, involved in chondrogenesis (Shinoda et al, 2008), displayed such biases in the DF-specific set (Figure 2A, right), which also significantly overlap (p < 0.05) KLF5 binding data (Tables S2 and S3) (Figure 2B for an example). We also observed in knee-specific sets a bias for alterations at predicted CTCF motifs, whose loss-of-function results in skeletal defects and spontaneous OA (Hijazi, 2018). Knee-specific sets also significantly overlap with CTCF binding data (Table S2) (Figure 2C for an example).…”

Section: Inter-species Sequence Variation In Element Setsmentioning

confidence: 54%

Evolutionary Selection and Constraint on Human Knee Chondrocyte Regulation Impacts Osteoarthritis Risk

Richard¹,

Liu²,

Cao³

et al. 2020

Cell

110

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During human evolution, the knee adapted to the biomechanical demands of bipedalism by altering chondrocyte developmental programs. This adaptive process was likely not without deleterious consequences to health. Today, osteoarthritis occurs in 250 million people, with risk variants enriched in non-coding sequences near chondrocyte genes, loci that likely became optimized during knee evolution. We explore this relationship by epigenetically profiling joint chondrocytes, revealing ancient selection and recent constraint and drift on knee regulatory elements, which also overlap osteoarthritis variants that contribute to disease heritability by tending to modify constrained functional sequence. We propose a model whereby genetic violations to regulatory constraint, tolerated during knee development, lead to adult pathology. In support, we discover a causal enhancer variant (rs6060369) present in billions of people at a risk locus (GDF5-UQCC1), showing how it impacts mouse knee-shape and osteoarthritis. Overall, our methods link an evolutionarily novel aspect of human anatomy to its pathogenesis.

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Section: Inter-species Sequence Variation In Element Setsmentioning

confidence: 54%