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Status |
Public on Feb 03, 2025 |
Title |
Pharmacological Modulation of BMAL1 Alters Circadian Dynamics and the Macrophage Immune Response |
Organism |
Mus musculus |
Experiment type |
Expression profiling by high throughput sequencing
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Summary |
The master transcription factor BMAL1-CLOCK is crucial for orchestrating rhythmic gene expression and governing circadian rhythms. Pharmacological manipulation of this central circadian regulator requires accessible protein cavities and selective compounds. By targeting BMAL1 through a resident cavity in its PAS-B domain, we demonstrate that the small-molecule Core Circadian Modulator (CCM) penetrates and substantially expands this pocket. Biochemical and cellular analyses validate CCM's target engagement selectivity, enabling direct access to BMAL1's transcriptional activities. CCM induces dose-dependent changes in PER2-Luc macrophage oscillations and selectively modifies expression patterns of circadian controlled genes. In activated macrophages, CCM modulates BMAL1-CLOCK controlled inflammatory and phagocytic pathways to promote their downregulation. Our findings demonstrate the feasibility of directly targeting BMAL1-CLOCK as a strategy for circadian regulation and targeting circadian-regulated processes
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Overall design |
To investigate the specificity and effects of pharmacological manipulation of Bmal1, bone-marrow derived macrophages from both myeloid cell specific Bmal1-KO mice and littermate controls were treated with CCM. The effect of inflammation was monitored: this was done under both basal and stimulated conditions.
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Contributor(s) |
Bailey L, Ray D |
Citation missing |
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Submission date |
Feb 08, 2024 |
Last update date |
Feb 03, 2025 |
Contact name |
Laura Bailey |
E-mail(s) |
laura.bailey@exeter.ox.ac.uk
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Organization name |
University of Oxford
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Department |
Oxford Centre for Diabetes, Endocrinology and Metabolism
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Street address |
Radcliffe Department of Medicine
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City |
Oxford |
ZIP/Postal code |
OX3 7LE |
Country |
United Kingdom |
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Platforms (1) |
GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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Samples (36)
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GSM8070294 |
BMDM, Bmal1-KO, Vehicle control, rep1 |
GSM8070295 |
BMDM, Bmal1-KO, LPS, rep2 |
GSM8070296 |
BMDM, Bmal1-KO, CCM, rep2 |
GSM8070297 |
BMDM, Bmal1-KO, LPS + CCM, rep2 |
GSM8070298 |
BMDM, Bmal1-KO, Vehicle control, rep2 |
GSM8070299 |
BMDM, Wild-type, LPS, rep1 |
GSM8070300 |
BMDM, Wild-type, CCM, rep1 |
GSM8070301 |
BMDM, Wild-type, LPS + CCM, rep1 |
GSM8070302 |
BMDM, Wild-type, Vehicle control, rep1 |
GSM8070303 |
BMDM, Wild-type, LPS, rep2 |
GSM8070304 |
BMDM, Wild-type, CCM, rep2 |
GSM8070305 |
BMDM, Wild-type, LPS + CCM, rep2 |
GSM8070306 |
BMDM, Wild-type, Vehicle control, rep2 |
GSM8070307 |
BMDM, Bmal1-KO, LPS, rep3 |
GSM8070308 |
BMDM, Bmal1-KO, CCM, rep3 |
GSM8070309 |
BMDM, Bmal1-KO, LPS + CCM, rep3 |
GSM8070310 |
BMDM, Bmal1-KO, Vehicle control, rep3 |
GSM8070311 |
BMDM, Bmal1-KO, LPS, rep4 |
GSM8070312 |
BMDM, Bmal1-KO, CCM, rep4 |
GSM8070313 |
BMDM, Bmal1-KO, LPS + CCM, rep4 |
GSM8070314 |
BMDM, Bmal1-KO, Vehicle control, rep4 |
GSM8070315 |
BMDM, Wild-type, LPS, rep3 |
GSM8070316 |
BMDM, Wild-type, CCM, rep3 |
GSM8070317 |
BMDM, Wild-type, LPS + CCM, rep3 |
GSM8070318 |
BMDM, Wild-type, Vehicle control, rep3 |
GSM8070319 |
BMDM, Bmal1-KO, LPS, rep5 |
GSM8070320 |
BMDM, Bmal1-KO, CCM, rep5 |
GSM8070321 |
BMDM, Bmal1-KO, LPS + CCM, rep5 |
GSM8070322 |
BMDM, Bmal1-KO, Vehicle control, rep5 |
GSM8070323 |
BMDM, Bmal1-KO, LPS, rep6 |
GSM8070324 |
BMDM, Bmal1-KO, CCM, rep6 |
GSM8070325 |
BMDM, Bmal1-KO, LPS + CCM, rep6 |
GSM8070326 |
BMDM, Bmal1-KO, Vehicle control, rep6 |
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Relations |
BioProject |
PRJNA1074737 |
Supplementary file |
Size |
Download |
File type/resource |
GSE255357_gene_count.txt.gz |
3.0 Mb |
(ftp)(http) |
TXT |
SRA Run Selector |
Raw data are available in SRA |
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