Macrophage Kdm6b Controls the Pro-Fibrotic Transcriptome Signature of Foam Cells

Abstract

Aim: In order to identify regulators of foam cells, we studied the H3K27 demethylase Kdm6b (also known as Jmjd3), a known regulator of macrophages, in controlling the transcriptional profile of foam cells. Materials & methods: Foam cells from Kdm6b-deleted or Kdm6b wild-type mice were isolated and used for RNA-sequencing analysis. Results: Pathway analysis revealed that pro-fibrotic pathways were strongly suppressed in Kdm6b-deleted foam cells. Analysis of published datasets showed that foam cell formation induces these pro-fibrotic characteristics. Overlay of both datasets indicated that fibrotic genes which are induced upon foam cell formation, are reduced in the absence of Kdm6b. These data suggest that foam cell formation induces a pro-fibrotic gene signature in a Kdm6b-dependent manner. Conclusion: We identified Kdm6b as a novel regulator of the pro-fibrotic signature of peritoneal foam cells.

Keywords::

• epigenetics
• fibrosis
• histone demethylase
• histone H3K27me3
• histone modification
• Jmjd3
• JmjdC
• Kdm6b
• macrophage
• matrix biology

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/full/10.2217/epi-2016-0152

Financial & competing interests disclosure

This work was mainly supported by The Netherlands Heart Foundation (CVON 2011/B019: Generating the best evidence-based pharmaceutical targets for atherosclerosis [GENIUS]). J Van den Bossche received a Junior Postdoc grant from The Netherlands Heart Foundation (2013T003) and a VENI grant from ZonMW (91615052). MPJ de Winther is an established investigator of The Netherlands Heart Foundation, is supported by a grant from The Netherlands Heart Foundation and Spark-Holding BV (2015B002), the European Union (ITN-grant EPIMAC) and holds an AMC-fellowship. MPJ de Winther and E Lutgens are both supported by REPROGRAM (EU Horizon 2020). The generation of Jmjd3 fl/fl mice was supported by the DFG (SFB834, project B5) to S Dimmeler. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

All animal experiments were conducted at the University of Amsterdam and approved (permit: DBC10AD) by the Committee for Animal Welfare of the Academic Medical Center, University of Amsterdam.

Additional information

Funding

This work was mainly supported by The Netherlands Heart Foundation (CVON 2011/B019: Generating the best evidence-based pharmaceutical targets for atherosclerosis [GENIUS]). J Van den Bossche received a Junior Postdoc grant from The Netherlands Heart Foundation (2013T003) and a VENI grant from ZonMW (91615052). MPJ de Winther is an established investigator of The Netherlands Heart Foundation, is supported by a grant from The Netherlands Heart Foundation and Spark-Holding BV (2015B002), the European Union (ITN-grant EPIMAC) and holds an AMC-fellowship. MPJ de Winther and E Lutgens are both supported by REPROGRAM (EU Horizon 2020). The generation of Jmjd3 fl/fl mice was supported by the DFG (SFB834, project B5) to S Dimmeler. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.