Dynamic gene regulation by nuclear colony-stimulating factor 1 receptor in human monocytes and macrophages

Laura Bencheikh,Sylvie Souquere,Aygun Imanci,Margot Morabito,Julie Rivière,Audrey Naimo,Nathalie Droin,Michaël Dussiot,Eric Solary,Gerard Pierron,M’Boyba Khadija Diop,Camille Lobry,Frédéric De Leeuw

doi:10.1038/s41467-019-09970-9

Abstract

Despite their location at the cell surface, several receptor tyrosine kinases (RTK) are also found in the nucleus, as either intracellular domains or full length proteins. However, their potential nuclear functions remain poorly understood. Here we find that a fraction of full length Colony Stimulating Factor-1 Receptor (CSF-1R), an RTK involved in monocyte/macrophage generation, migrates to the nucleus upon CSF-1 stimulation in human primary monocytes. Chromatin-immunoprecipitation identifies the preferential recruitment of CSF-1R to intergenic regions, where it co-localizes with H3K4me1 and interacts with the transcription factor EGR1. When monocytes are differentiated into macrophages with CSF-1, CSF-1R is redirected to transcription starting sites, colocalizes with H3K4me3, and interacts with ELK and YY1 transcription factors. CSF-1R expression and chromatin recruitment is modulated by small molecule CSF-1R inhibitors and altered in monocytes from chronic myelomonocytic leukemia patients. Unraveling this dynamic non-canonical CSF-1R function suggests new avenues to explore the poorly understood functions of this receptor and its ligands.

Highlights

Despite their location at the cell surface, several receptor tyrosine kinases (RTK) are found in the nucleus, as either intracellular domains or full length proteins
Colony Stimulating Factor-1 Receptor (CSF-1R) localization was observed by electron microscopy in heterochromatin and euchromatin (Fig. 1f), which was validated by a distinct antibody targeting CSF-1R N-terminal fragment (Supplementary Fig. 1d)
These results demonstrate the presence of a fraction of full-length CSF-1R in human monocyte nucleus

Summary

Introduction

Despite their location at the cell surface, several receptor tyrosine kinases (RTK) are found in the nucleus, as either intracellular domains or full length proteins Their potential nuclear functions remain poorly understood. Upon CSF-1 exposure, which induces monocyte differentiation into macrophages, CSF-1R localization on chromatin changes within a few hours, it colocalizes with H3K4me[3], and promotes gene expression through interaction with transcription factors YY1 and ELK. This function is affected by small molecule CSF-1R inhibitors and altered in dysplastic monocytes collected from chronic myelomonocytic leukemia (CMML) patients. These results emphasize a dynamic role of nuclear CSF-1R in monocyte differentiation into macrophages

Methods

Results

Conclusion