Abstract
The coactivator-associated arginine methyltransferase (CARM1) functions as a regulator of transcription by methylating a diverse array of substrates. To broaden our understanding of CARM1's mechanistic actions, we sought to identify additional substrates for this enzyme. To do this, we generated CARM1 substrate motif antibodies, and used immunoprecipitation coupled with mass spectrometry to identify cellular targets of CARM1, including mediator complex subunit 12 (MED12) and the lysine methyltransferase KMT2D. Both of these proteins are implicated in enhancer function. We identified the major CARM1-mediated MED12 methylation site as arginine 1899 (R1899), which interacts with the Tudor domain-containing effector molecule, TDRD3. Chromatin immunoprecipitation-seq studies revealed that CARM1 and the methyl mark it deposits are tightly associated with ERα-specific enhancers and positively modulate transcription of estrogen-regulated genes. In addition, we showed that the methylation of MED12, at the R1899 site, and the recruitment of TDRD3 by this methylated motif are critical for the ability of MED12 to interact with activating noncoding RNAs.
Highlights
In humans, approximately 100,000 hematopoietic stem cells (HSCs) produce 100 billion blood cells a day (Lee-Six et al, 2018)
We show that monocytopenia precedes neutropenia by 3 days, and rationalize the use of GCSF during chemotherapy by establishing that the onset of monocytopenia can be used as a clinical marker for granulocyte colony-stimulating factor (G-CSF) dosing post-chemotherapy
We investigate the impact of G-CSF support of the granulocyte-macrophage lineage during chemotherapy, with a particular emphasis on its effects on monocytopenia to inform the use of GCSF during cyclic cytotoxic chemotherapy
Summary
Approximately 100,000 hematopoietic stem cells (HSCs) produce 100 billion blood cells a day (Lee-Six et al, 2018). Smith et al (Smith, 2011) developed a mathematical model for the resolution of pneumonia infection in mice that included three distinct phases of the immune response to pneumonia, including the immune response from tissue resident macrophages and cytokine driven recruitment of circulating neutrophils, and the role of MDMs in infection clearance. Marino et al (Marino et al, 2015) studied the role of macrophage polarization in M.tuberculosis infection While these models underscore the importance of MDMs in the resolution of infection, their focus was primarily on the site of infection and did not describe the regulation of the production of neutrophils and monocytes in the bone marrow, assuming cytokine- or neutrophil-driven recruitment instead. Our results have potentially significant clinical implications as they suggest that the arrival of the monocyte nadir can be used as an indicator to mitigate neutropenia through exogenous G-CSF administration
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