Extended Data Fig. 10: Reduction of 5hmC in SMCs leads to formation of spurious transcripts, causing phenotype switching, TLR7 activation, and airway inflammation.
From: Spurious transcription causing innate immune responses is prevented by 5-hydroxymethylcytosine
a, Proposed model of the role of TET3 and 5hmC in transcriptional regulation. TET3 interacts with Pol II during transcriptional elongation and deposits 5hmC in actively transcribed genes when methylated cryptic starts sites (TSSs) or transposons are encountered. TET3 and/or 5hmC stabilize recruitment of SETD2 to the Pol II containing elongation machinery, which leads to increased formation of H3K36me3, preventing ectopic entry of Pol II and thereby enforcing usage of canonical, upstream promoters. Complete oxidation of 5hmC leading to demethylation might result in de-novo formation of 5mC, essentially resetting the chromatin for another round of transcriptional elongation. b, Depiction of the function of TET3 in SMCs. TET3-mediated formation of 5hmC in SMCs prevents intragenic entry of Pol II pSer5, aberrant transcriptional initiation within highly transcribed genes, and activation of TLR7 signaling. Reduction of 5hmC due to the absence of TET3 causes intragenic entry of Pol II that reduces production of contractile proteins and initiates formation of spurious transcripts, which activate endosomal TLR7 signaling and results in a phenotype switch in SMCs from the contractile to the synthetic state. Ongoing activation of innate immune responses and the phenotype switch in SMCs will provoke a T helper type 2 (Th2) cell-based immune response that accounts for the massive inflammation and pathology of Tet3-deficient airways.
