N6-methyladenosine modification in chronic stress response due to social hierarchy positioning of mice

Appropriately responding to stressful events is important for maintaining health and well-being of an organism. With respect to social stress, the response is not always as straightforward as reacting to physical stressors, e.g. extreme heat, and thus has to be balanced subtly. Particularly, regulatory mechanisms contributing to gaining resilience in the face of mild social stress are not fully deciphered yet. We employed an intrinsic social hierarchy stress paradigm in mice of both sex to identify key factors for coping strategies. While global transcriptomic changes could not be observed in male mice, several genes which were previously reported to be involved in synaptic plasticity, learning and anxiety-like behavior were differentially regulated in female mice. Moreover, changes in N6-methyladenosine-modification of mRNA associated with corticosterone level occurred. Further investigation of proteins involved in m6A modification revealed that no significant changes of amount or activity could be detected for male mice. However, METTL3 and WTAP, subunits of the methyltransferase complex, showed elevated levels in female mice. N6-adenosyl-methylation is the most prominent type of mRNA methylation and plays a crucial role in processes such as metabolism, but also response to physical stress. Our findings underpin its important role by attributing it also to social stress evoked by hierarchy building within same-sex groups. Comparison of brain right hemisphere transcriptomic profile of dominant and submissive male and female mice. Please note that the processed data columns correspond to the samples as below: um_endres_2018_01_01_1394-D2_S1 = Dominant male 1 um_endres_2018_01_03_1395-D2_S3 = Dominant male 2 um_endres_2018_01_05_1396-D1_S5 = Dominant male 3 um_endres_2018_01_07_1397-D2_S7 = Dominant male 4 um_endres_2018_01_09_1398-D1_S9 = Dominant male 5 um_endres_2018_01_11_1399-D1_S11 = Dominant male 6 um_endres_2018_01_13_1400-D3_S13 = Dominant male 7 um_endres_2018_01_02_1394-S3_S2 = Submissive male 1 um_endres_2018_01_04_1395-S4_S4 = Submissive male 2 um_endres_2018_01_06_1396-S2_S6 = Submissive male 3 um_endres_2018_01_08_1397-S4_S8 = Submissive male 4 um_endres_2018_01_10_1398-S2_S10 = Submissive male 5 um_endres_2018_01_12_1399-S2_S12 = Submissive male 6 um_endres_2018_01_14_1400-S1_S14 = Submissive male 7 jgu_gerber_2018_01_07_01279-3_dominant_S7 = Dominant female 1 jgu_gerber_2018_01_10_01280-2_dominant_S10 = Dominant female 2 jgu_gerber_2018_01_11_Gr1-4_dominant_S11 = Dominant female 3 jgu_gerber_2018_01_13_Gr2-4_dominant_S13 = Dominant female 4 jgu_gerber_2018_01_08_01279-4_submissive_S8 = Submissive female 1 jgu_gerber_2018_01_09_01280-1_submissive_S9 = Submissive female 2 jgu_gerber_2018_01_12_Gr1-3_submissive_S12 = Submissive female 3 jgu_gerber_2018_01_14_Gr2-2_submissive_S14 = Submissive female 4