During cardiac remodeling caused by chronic pressure overload, various cardiac cell populations modulate the inflammatory response. While the role of cardiac myocytes and fibroblasts has been well characterized, the distinct functions of cardiac resident macrophages are yet to be uncovered.

RNASeq and single-cell sequencing data from our lab identified a highly enriched and abundant lncRNA which was also de-regulated during disease (pressure-overload of the left ventricle). This lncRNA was termed Schlafenlnc due to its localization in the Schlafen protein family locus. In vitro experiments on Schlafenlnc-deficient macrophages (generated by CRISPR/Cas9) showed a significantly impaired migration and chemotaxis. 

To study the in vivo function of Schlafenlnc, we generated a mouse line with a genetic deletion of the Schlafenlnc locus using the CRISPR/Cas9 system. sgRNA cutting sites were introduced based on histone modifications (e.g. H3K4m3) from bone marrow-derived macrophages defining the promoter region as well as the full gene body. The successful deletion was measured by genotyping PCR as well as on a transcriptional level using qPCR. Schlafenlnc-deficient mice were fertile. However, litter sizes were reduced (average 4,37 pups per breeding) compared to the wild type Black6 strain. Knockout animals were born within the expected mendelian quantity. Preliminary experiments of Schlafenlnc-deficient mice showed a reduced number (approx. by 50%) of resident macrophages within the heart. This reduction suggests that recruitment of macrophages or monocytes to the heart were impaired by loss of Schlafenlnc. We are currently phenotyping all aspects of cardiac parameters in this mouse line (heart weight, ejection fraction, number and distribution of macrophages etc.) in health as well as during pressure overload (transverse aortic constriction (TAC) model). Our results provide insight into relevant mechanisms of lncRNA-dependent modulation of cardiac macrophage function.