A Long Noncoding RNA Amerliorates Periodontitis via Distinct Epigenetic Pathways

Nearly 50% of American adults over age 30 have periodontal disease (PD). The basic pathology of PD
is excessive alveolar bone resorption leading to tooth loss. Furthermore, PD can trigger general inflammation,
adversely influencing cardiovascular, central nervous, reproductive and endocrine systems. Our laboratory has
explored a variety of strategies for treating this disease and is still actively searching for a more effective and
practical therapy with minimal side effects to cure the disease. Long noncoding RNAs (lncRNAs) are a family of
non-protein-coding transcripts with the length longer than 200 nucleotides. LncRNAs participate in a wide
repertoire of biological processes and play important roles in gene expression and posttranscriptional processes
and are also implicated in the pathogenesis of many diseases. However, the functions of lncRNAs in dental
diseases are just beginning to be uncovered. LncRNA ANRIL was the first shared genetic risk factor of
atherosclerosis, PD, diabetes and cancers, thereby coined to APCD. Our laboratory has performed extensive
preliminary studies including studies on lncRNA-APDC knockout mice. Our hypothesis is that lncR-APDC
inhibits inflammation, osteoclastic bone resorption and promotes osteogenesis and alveolar bone regeneration
through specific epigenetic pathways, by which efficiently targeting the pathophysiology of periodontitis. Aim 1
will determine the functions of lncR-APDC in periodontitis via loss- and gain-of-function approaches. Next
generation RNA-Seq will be performed to elucidate the expression patterns of the participating genes and cellular
pathways altered by the lncRNA dysregulation. Aim 2 will use state-of-the-art techniques to determine the
cellular localization of lncR-APDC and decipher the mechanisms by characterizing the protein and RNA binding
partners and chromosomal regions regulated by the lncR-APDC. Aim 3 will test the therapeutic effects of lncR-
APDC in periodontitis to determine lncR-APDC’s effect on inflammation, osteoclastic bone resorption and
alveolar bone regeneration. The results will provide a paradigm shift and advance the research field vertically in
three ways. Firstly, we have initially found that lncR-APDC could play a pivotal role in cell differentiation and
proliferation in PD. However, how this lncRNA is involved in PD progression is virtually unknown. Therefore, the
results will reveal a novel pathological mechanism of PD deterioration and progression. Secondly, we will
decipher the pathways of lncR-APDC modulating gene clusters in different cells playing active roles in the
periodontal microenvironment and their roles in the PD progression, which will lead to the discovery of novel
therapeutic targets. Finally, we will examine the potential utility of our newly constructed adenovirus conjugated
lncR-APDC, as a safe and effective therapeutic measure for PD in dental clinics. An interdisciplinary team of
investigators with complementary and synergistic skills will conduct the studies (Jake Chen – Experimental Oral
Pathology and Bone Biology; Qisheng Tu – Cell and Molecular Biology; Thomas Van Dyke – Periodontology
and RNA-Sequencing; Hans Johansson – RNA Biology and lncRNA FISH).

Grant Number: 5R01DE030074-05
NIH Institute/Center: NIH
Principal Investigator: JAKE CHEN