Tissue-Resident Macrophage Enhancer Landscapes Are Shaped by the Local Microenvironment

Abstract

SUMMARY Macrophages are critical for innate immune defense and also control organ homeostasis in a tissue-specific manner. They provide a fitting model to study the impact of ontogeny and microenvironment on chromatin state and whether chromatin modifications contribute to macrophage identity. Here, we profile the dynamics of four histone modifications across seven tissue-resident macrophage populations. We identify 12,743 macrophage-specific enhancers and establish that tissue-resident macrophages have distinct enhancer landscapes beyond what can be explained by developmental origin. Combining our enhancer catalog with gene expression profiles and open chromatin regions, we show that a combination of tissue- and lineage-specific transcription factors form the regulatory networks controlling chromatin specification in tissue-resident macrophages. The environment is capable of shaping the chromatin landscape of transplanted bone marrow precursors, and even differentiated macrophages can be reprogramed when transferred into a new microenvironment. These results provide a comprehensive view of macrophage regulatory landscape and highlight the importance of the micro-environment, along with pioneer factors in orchestrating identity and plasticity.

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“…Moreover, ATMs failed to show clustering with macrophages from liver, lung, brain, peritoneum or intestines (Extended Data. 3e), consistent with specialized function of ATMs 16 . Furthermore, co-expression analysis identified 1,887 highly connected genes with age, which were visualized as a network (Extended Data 4a, b).…”

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“…Moreover, another study compiled a comprehensive catalog of enhancer histone marks at the single‐cell level, and unveiled that there exists significant de novo establishment of lineage‐specific enhancers during hematopoiesis 25. Similarly, based on single‐cell profiling of histone modifications dynamics in different tissue‐resident macrophages populations, the same group showed that a combination of tissue‐ and lineage‐specific transcription factors form the regulatory networks controlling chromatin specification in tissue‐resident macrophages 26.…”

“…This field has been propelled by remarkable technological advances for efficiently isolating single cells 28, 29, and the reduction of the detection levels of protocols for profiling gene expression 30, 31, histone marks 25, 26, or chromatin accessibility 32, 33 in individual cells. These techniques allow researchers to overcome the limitations of population studies, in which averaging the measurements over a heterogeneous population of cells masks the variability at the epigenetics and transcriptional levels among cells within a culture or tissue 26, 34, 35. Moreover, the analysis of large numbers of single cells provides statistical power for predicting functional correlations among genes 36 in different cells within a heterogeneous population, hence facilitating the reconstruction of subpopulation‐specific gene regulatory networks that determine priming for commitment to different cell fates.…”

“…These network models 73, 74, 102, 103 relying solely on transcriptomics data could be significantly improved by overlaying epigenetics data 25, 32, 33, for contextualizing regulatory interactions at the transcriptional level depending on the chromatin state – e.g. open/close chromatin regions, and activating/inhibitory chromatin marks patterns 25, 26, 32, 33. Moreover, although it is not yet possible to perform single cell measurements of signaling pathways, the inclusion of phosphoproteomics data in these network models will include another layer of information for contextualizing network interactions in this layer, depending on the post‐translational modifications determining the activity of signalling proteins 105, 106.…”

“…Since the characterization of the initial PGRNs, more complex regulatory networks have been described including many other transcription factors (TFs) ( Sall4 , Zscan10 , and Dax1 ) as key regulators of self‐renewal and differentiation of ESCs into different cell‐fates 4, 24. The chromatin landscape and signaling pathways also play a key role in regulating pluripotency and differentiation, although the cross talk between these regulatory levels during lineage specification has been much less studied 5, 25, 26.…”