Scientific RepoRts | 7: 191 | DOI:10.1038/s41598-017-00301-w
MKL1 denes the H3K4Me3
landscape for NF-κB dependent
, Fei Fang
, Xin Dai
, Huihui Xu
, Xiaohong Qi
, Mingming Fang
& Yong Xu
Macrophage-dependent inammatory response is considered a pivotal biological process that
contributes to a host of diseases when aberrantly activated. The underlying epigenetic mechanism
is not completely understood. We report here that MKL1 was both sucient and necessary for p65-
dependent pro-inammatory transcriptional program in immortalized macrophages, in primary
human and mouse macrophages, and in an animal model of systemic inammation (endotoxic shock).
Extensive chromatin immunoprecipitation (ChIP) proling and ChIP-seq analyses revealed that MKL1
deciency erased key histone modications synonymous with transactivation on p65 target promoters.
Specically, MKL1 dened histone H3K4 trimethylation landscape for NF-κB dependent transcription.
MKL1 recruited an H3K4 trimethyltransferase SET1 to the promoter regions of p65 target genes. There,
our work has identied a novel modier of p65-dependent pro-inammatory transcription, which may
serve as potential therapeutic targets in treating inammation related diseases.
A balanced immune response is paramount to the homeostasis whereas deregulated immunity engenders chronic
inammation and is blamed for the pathogenesis of a host of disease states in humans
. Regardless of the nature of
the stimuli, the twists and turns of cellular immune response invariably settle on a transcriptional network spear-
headed by a few evolutionarily conserved transcription factors among which NF-κB is considered the master
regulator of pro-inammatory transcription
. To ensure an immune response of desired magnitude, the intensity
and duration of NF-κB dependent transcription is tightly controlled. NF-κB tailors pro-inammatory transcrip-
tion programs by forging extensive protein-protein interactions with its binding partners that in turn modulate
its subcellular localization
, post-translational modications
, and/or chromatin structure of its target promoters
Mounting evidence has highlighted the importance of the epigenetic machinery in fine-tuning NF-κB
dependent inammatory response. Several recent reports have implicated histone H3K4 methyltransferases,
, and SET7/9
, as essential for the transactivation of a subset of NF-κB target
genes. Alternatively, SMYD5 mediated methylation of H4K20 has been proposed as a repressive signature that
halts the transcription of pro-inammatory genes downstream of TLR4 signaling
. erefore, a consensus seems
to be building up that chromatin structure is a pivotal determinant of NF-κB driven transcription.
Rel-A/p65 is the most well studied member of the NF-κB family primarily forming a heterodimer with p50
that represents a key node in the intertwined inammatory circuit
. Our previous publication has characterized
a physical interaction between p65 and megakyrocytic leukemia 1 (MKL1)
. MKL1, also known as myocardin
related transcription factor A (MRTF-A), was initially identied as a co-factor for SRF involved in the transcrip-
tional regulation of smooth muscle contraction genes
. Unlike myocardin that shows a muscle-restricted expres-
sion pattern, MKL1 is universally expressed
. MKL1 regulates transcription and, by extension, cellular processes
by interacting with sequence-specic transcription factors including SMAD3
. Recently, a number of independent investigations have pitched MKL1 as a potential stress protein that
links specic transcription event(s) to cellular adaptation to cardiovascular risk factors
. Based on these nd-
ings, we asked whether and if so how MKL1 modies p65 dependent pro-inammatory transcriptional program.
Our data presented here suggest that MKL serves as a coordinator dening the epigenetic landscape for p65.
Key Laboratory of Cardiovascular Disease and Key Laboratory of Human Functional Genomics of Jiangsu Province,
Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
State Key Laboratory of Nature
Medicines, China Pharmaceutical University, Nanjing, China. Liming Yu, Fei Fang and Xin Dai contributed equally to
this work. Correspondence and requests for materials should be addressed to M.F. (email: firstname.lastname@example.org) or
Y.X. (email: email@example.com)
Received: 13 July 2016
Accepted: 17 February 2017
Published: xx xx xxxx