[4] The BMAL1 protein is 626 amino acids long and plays a key role as one of the positive elements in the mammalian auto-regulatory transcription-translation negative feedback loop (TTFL), which is responsible for generating molecular circadian rhythms.

[5] BMAL1 has also been identified as a candidate gene for susceptibility to hypertension, diabetes, and obesity,[6][7] and mutations in BMAL1 have been linked to infertility, gluconeogenesis and lipogenesis problems, and altered sleep patterns.

[9] The BMAL1 gene was originally discovered in 1997 by two groups of researchers, John B. Hogenesch et al. in March under the name MOP3 [10] and Ikeda and Nomura in April[11] as part of a superfamily of PAS domain transcription factors.

One of BMAL1 protein's earliest discovered functions in circadian regulation was related to the CLOCK-BMAL1 (CLOCK-ARNTL) heterodimer, which would bind through an E-box enhancer to activate the transcription of the AVP gene which encodes for vasopressin.

[16] In addition to the circadian regulatory TTFL loop, Bmal1 transcription is regulated by competitive binding to the retinoic acid-related orphan receptor response element-binding site (RORE) within the promoter of Bmal1.

The CLOCK/BMAL1 heterodimer also binds to E-box elements in promoter regions of Rev-Erbα and RORα/ß genes, upregulating transcription and translation of REV-ERB and ROR proteins.

Other nuclear receptors of the same families (NR1D2 (Rev-erb-β); NR1F2 (ROR-β); and NR1F3 (ROR-γ)) have also been shown to act on Bmal1 transcriptional activity in a similar manner.

[27] This suggests that the opposing activities of the orphan nuclear receptors RORA and REV-ERBα, the latter of which represses Bmal1 expression, are important in the maintenance of circadian clock function.

[33] Recent phenotype data also suggest this gene[34] and its partner Clock[35] play a role in the regulation of glucose homeostasis and metabolism, which can lead to hypoinsulinaemia or diabetes when disrupted.

[36] In regards to other functions, another study shows that the CLOCK/BMAL1 complex upregulates human LDLR promoter activity, suggesting the Arntl gene also plays a role in cholesterol homeostasis.

[43] Lastly, BMAL1 has been identified through functional genetic screening as a putative regulator of the p53 tumor suppressor pathway suggesting potential involvement in the circadian rhythms exhibited by cancer cells.

T cell or myeloid-specific deletion of Bmal1 has been shown to cause more severe pathology and is sufficient to abolish the rest vs. active induction effect.

[60] Shift work and chronic jet lag have been suggested to correlate with outcomes such as preterm labor, low birth weight, and gestational diabetes.

[61] Gene knockout models in mice have helped to understand the role Bmal1 has in transcriptional translational feedback loops and the effects of its absence on circadian rhythms and other physiological processes.

It is a point of sensitivity within the network, as it is the only gene whose single knockout in a mouse model generates arrhythmicity at both the molecular and behavioral levels.

By loss of Ccl2 regulation, BMAL1 KO in myeloid cells results in hindered monocyte recruitment, pathogen clearance, and anti-inflammatory response (consistent with the arthropathy phenotype).

[74] Finally, BMAL1 interactions with HSF1 triggers clock synchronization and the release of pro-survival factors, highlighting the contribution of BMAL1 to cell stress and survival responses.

[75] BMAL1 deficient hESC-derived cardiomyocytes exhibited typical phenotypes of dilated cardiomyopathy including attenuated contractility, calcium dysregulation, and disorganized myofilaments.