Details for: BMAL2

Gene ID: 56938

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: BMAL2

Ensembl ID: ENSG00000029153

Description: basic helix-loop-helix ARNT like 2

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • L2/3-6 intratelencephalic projecting glutamatergic neuron CL4023040
    CSI 8.68
    rCSI 21.09%
    PRS 75.47
  • near-projecting glutamatergic cortical neuron CL4023012
    CSI 8.29
    rCSI 31.34%
    PRS 77.88
  • L6b glutamatergic cortical neuron CL4023038
    CSI 4.66
    rCSI 14.56%
    PRS 79.01
  • blood vessel endothelial cell CL0000071
    CSI 4.11
    rCSI 8.52%
    PRS 88.85
  • cerebral cortex endothelial cell CL1001602
    CSI 3.59
    rCSI 6.22%
    PRS 85.19
  • respiratory suprabasal cell CL4033048
    CSI 3.29
    rCSI 4.22%
    PRS 92.11
  • multi-ciliated epithelial cell CL0005012
    CSI 3.08
    rCSI 3.07%
    PRS 85.04
  • hepatocyte CL0000182
    CSI 3.06
    rCSI 5.47%
    PRS 89.16
  • respiratory hillock cell CL4030023
    CSI 3
    rCSI 5.35%
    PRS 94.15
  • adipocyte CL0000136
    CSI 2.81
    rCSI 3.61%
    PRS 82.46
  • sst GABAergic cortical interneuron CL4023017
    CSI 2.81
    rCSI 3.62%
    PRS 78.77
  • conjunctival epithelial cell CL1000432
    CSI 2.78
    rCSI 4.25%
    PRS 89.7
  • pvalb GABAergic cortical interneuron CL4023018
    CSI 2.72
    rCSI 3.39%
    PRS 75.5
  • intrahepatic cholangiocyte CL0002538
    CSI 2.67
    rCSI 6.42%
    PRS 90.68
  • mucus secreting cell CL0000319
    CSI 2.58
    rCSI 4.09%
    PRS 94.58
  • lamp5 GABAergic cortical interneuron CL4023011
    CSI 2.43
    rCSI 4.08%
    PRS 77.68
  • GABAergic neuron CL0000617
    CSI 2.38
    rCSI 7.96%
    PRS 77.27
  • VIP GABAergic cortical interneuron CL4023016
    CSI 2.36
    rCSI 2.82%
    PRS 77.77
  • squamous epithelial cell CL0000076
    CSI 2.04
    rCSI 4.85%
    PRS 87.81
  • pancreatic ductal cell CL0002079
    CSI 1.76
    rCSI 3.42%
    PRS 92
  • L4 intratelencephalic projecting glutamatergic neuron CL4030063
    CSI 1.72
    rCSI 4.11%
    PRS 80.39
  • sncg GABAergic cortical interneuron CL4023015
    CSI 1.59
    rCSI 2.55%
    PRS 78.67
  • corticothalamic-projecting glutamatergic cortical neuron CL4023013
    CSI 1.56
    rCSI 9.18%
    PRS 78.11
  • pancreatic acinar cell CL0002064
    CSI 1.5
    rCSI 2%
    PRS 93.22
  • basal cell of prostate epithelium CL0002341
    CSI 1.47
    rCSI 4.25%
    PRS 92.75
  • retinal ganglion cell CL0000740
    CSI 1.39
    rCSI 3.07%
    PRS 80.09
  • serotonergic neuron CL0000850
    CSI 1.25
    rCSI 5.59%
    PRS 76.39
  • L5/6 near-projecting glutamatergic neuron CL4030067
    CSI 1.07
    rCSI 3.5%
    PRS 79.22
  • dopaminergic neuron CL0000700
    CSI 1
    rCSI 5.64%
    PRS 79.98
  • L5 extratelencephalic projecting glutamatergic cortical neuron CL4023041
    CSI 0.96
    rCSI 3.45%
    PRS 75.64
  • direct pathway medium spiny neuron CL4023026
    CSI 0.78
    rCSI 18.68%
    PRS 75.47
  • indirect pathway medium spiny neuron CL4023029
    CSI 0.71
    rCSI 17.24%
    PRS 75.61
  • central nervous system neuron CL2000029
    CSI 0.7
    rCSI 5.17%
    PRS 82.3
  • medium spiny neuron CL1001474
    CSI 0.28
    rCSI 2.37%
    PRS 82.6
  • epithelial cell of urethra CL1000296
    CSI 0.24
    rCSI 5.94%
    PRS 93.11

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

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Comma-separated if multiple.
Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [BMAL2](/details-gene/56938) (basic helix-loop-helix ARNT like 2) is a protein-coding gene that encodes a transcription factor belonging to the bHLH-PAS superfamily. As a core component of the molecular clock, its primary function is the regulation of circadian rhythms and the rhythmic expression of downstream genes. The expression landscape of [BMAL2](/details-gene/56938) highlights a particularly significant role within the central nervous system, where it is a key marker for several subtypes of glutamatergic cortical neurons. Beyond the brain, it is also significantly expressed in diverse cell types including endothelial cells, various epithelial cells, and metabolically active cells such as [hepatocyte](/details-cell/CL0000182)s and [adipocyte](/details-cell/CL0000136)s, suggesting its role in maintaining circadian homeostasis across multiple tissues. ## Cellular Roles and Expression Landscape The **Overall** expression profile of [BMAL2](/details-gene/56938) reveals its prominent and specific role in the cerebral cortex. It demonstrates exceptionally high significance in excitatory neurons, including [L2/3-6 intratelencephalic projecting glutamatergic neuron](/details-cell/CL4023040) (CSI: 8.68), [near-projecting glutamatergic cortical neuron](/details-cell/CL4023012) (CSI: 8.29), and [L6b glutamatergic cortical neuron](/details-cell/CL4023038) (CSI: 4.66). Its significance extends to inhibitory interneurons as well, such as [sst GABAergic cortical interneuron](/details-cell/CL4023017) and [pvalb GABAergic cortical interneuron](/details-cell/CL4023018), indicating a broad involvement in regulating the rhythmic activity of cortical circuits. Beyond the nervous system, [BMAL2](/details-gene/56938) is also significantly expressed in several other key cell populations: * **Vascular Endothelium:** It is a significant marker in [blood vessel endothelial cell](/details-cell/CL0000071) and [cerebral cortex endothelial cell](/details-cell/CL1001602), suggesting a role in regulating the circadian functions of the vasculature. * **Epithelial Tissues:** Expression is noted in barrier and secretory cells like [respiratory suprabasal cell](/details-cell/CL4033048), [multi-ciliated epithelial cell](/details-cell/CL0005012), and [conjunctival epithelial cell](/details-cell/CL1000432), consistent with the known circadian control of epithelial biology. * **Metabolic Tissues:** Its significance in [hepatocyte](/details-cell/CL0000182), [adipocyte](/details-cell/CL0000136), and [intrahepatic cholangiocyte](/details-cell/CL0002538) underscores its role in orchestrating daily metabolic cycles in peripheral organs. ## Pathways and Molecular Function The functional annotations for [BMAL2](/details-gene/56938) firmly establish it as a core component of the circadian clock machinery. Its involvement in biological processes such as [circadian regulation of gene expression](/details-go/GO:0032922) and [circadian rhythm](/details-go/GO:0007623) is central to its function. As a transcription factor, its molecular activities include [DNA-binding transcription factor activity](/details-go/GO:0003700) and [E-box binding](/details-go/GO:0070888), which are characteristic of clock proteins that regulate target gene expression. Cellularly, [BMAL2](/details-gene/56938) localizes to the [nucleus](/details-go/GO:0005634) where it forms a heterodimeric complex, the [clock-bmal transcription complex](/details-go/GO:1990513), with other clock proteins like CLOCK or NPAS2. This complex drives the transcriptional feedback loops that constitute the molecular oscillator, as detailed in the [Circadian clock](/details-reactome/R-HSA-400253) pathway. This fundamental timekeeping role is consistent with its broad expression in physiologically active cells like neurons and hepatocytes, which rely on precise temporal regulation. Several studies have confirmed its ability to form functional heterodimers and regulate circadian gene expression, such as plasminogen activator inhibitor-1 ([Link](https://doi.org/10.1074/jbc.c000629200), [Link](https://doi.org/10.1016/s0022-2828(03)00051-8)). ## Research Directions Based on its function as a core clock component and its distinct expression profile, several research avenues can be explored to further elucidate the specific roles of [BMAL2](/details-gene/56938). **Proposed Hypotheses:** 1. Given its exceptionally high significance in diverse cortical neuron subtypes, we hypothesize that [BMAL2](/details-gene/56938) plays a specialized role in orchestrating the daily rhythms of synaptic function and plasticity in the cerebral cortex. Its dysregulation may contribute to altered excitation-inhibition balance underlying certain neurological or psychiatric disorders with circadian features. 2. The significant expression of [BMAL2](/details-gene/56938) in [hepatocyte](/details-cell/CL0000182)s and [adipocyte](/details-cell/CL0000136)s suggests it is a key regulator of peripheral metabolic clocks. We hypothesize that [BMAL2](/details-gene/56938) directly binds to the promoters of and regulates the rhythmic expression of key enzymes in glucose and lipid metabolism, and that loss of [BMAL2](/details-gene/56938) function in these cells could decouple systemic metabolic rhythms from the central clock, contributing to phenotypes associated with metabolic syndrome. **Experimental Approach:** To test the first hypothesis regarding the role of [BMAL2](/details-gene/56938) in cortical neurons, a conditional knockout mouse model could be generated using a Cre-loxP system with a forebrain-specific promoter (e.g., *Camk2a*-Cre). The direct impact on synaptic function could be assessed by performing time-course electrophysiological recordings (e.g., whole-cell patch-clamp) from cortical slices at distinct circadian time points to measure rhythmic changes in miniature excitatory and inhibitory postsynaptic currents (mEPSCs/mIPSCs). This functional analysis could be complemented by RNA-sequencing and chromatin immunoprecipitation sequencing (ChIP-seq) on sorted cortical neurons across the 24-hour cycle to identify the direct, rhythmically-regulated gene targets of [BMAL2](/details-gene/56938) that are involved in synaptic transmission. **Therapeutic Potential:** As an intranuclear transcription factor, [BMAL2](/details-gene/56938) represents a challenging therapeutic target for traditional small molecule inhibitors. However, modulating the circadian clock is a promising strategy for a range of disorders, including sleep-wake disorders, metabolic syndrome, and certain cancers. Rather than direct inhibition, therapeutic approaches might focus on modulating its activity or stability, for instance by targeting its protein-protein interaction interfaces with partners like CLOCK/NPAS2. Given its widespread expression, systemic modulation could have significant off-target effects. Therefore, the development of tissue-specific delivery systems or strategies aimed at restoring, rather than simply inhibiting, rhythmic [BMAL2](/details-gene/56938) activity may hold greater therapeutic promise.

Genular Protein ID: 249771936

Symbol: BMAL2_HUMAN

Name: Aryl hydrocarbon receptor nuclear translocator-like protein 2

UniProtKB Accession Codes:

Q8WYA1 B7Z429 F5H402 Q8WYA2 Q8WYA3 Q8WYA4 Q96J63 Q9H2M4 Q9NS70 Q9NYQ4 Q9NYQ5

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 6 CDD 2 CTD 1 ChiTaRS 1 ComplexPortal 1 DMDM 1 DNASU 1 DisGeNET 1 EMBL 14 Ensembl 7 EvolutionaryTrace 1 ExpressionAtlas 1 GO 20 Gene3D 2 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 7 KEGG 1 MANE-Select 1 MIM 1 MassIVE 1 NCBI Taxonomy 1 NCBIfam 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PDB 1 PDBsum 1 PRINTS 1 PRO 1 PROSITE 2 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 3 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 9 RNAct 1 Reactome 1 RefSeq 5 SIGNOR 1 SMART 2 SMR 1 STRING 1 SUPFAM 2 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 10964693

Title: cDNA cloning of a novel bHLH-PAS transcription factor superfamily gene, BMAL2; Its mRNA expression, subcellular distribution, and chromosomal localization.

PubMed ID: 10964693

DOI: 10.1006/bbrc.2000.3248

PubMed ID: 11018023

Title: CLIF, a novel cycle-like factor, regulates the circadian oscillation of plasminogen activator inhibitor-1 gene expression.

PubMed ID: 11018023

DOI: 10.1074/jbc.c000629200

PubMed ID: 10864977

Title: The basic helix-loop-helix-PAS protein MOP9 is a brain-specific heterodimeric partner of circadian and hypoxia factors.

PubMed ID: 10864977

DOI: 10.1523/jneurosci.20-13-j0002.2000

PubMed ID: 11554928

Title: Chicken pineal clock genes: implication of BMAL2 as a bidirectional regulator in circadian clock oscillation.

PubMed ID: 11554928

DOI: 10.1046/j.1365-2443.2001.00462.x

PubMed ID: 14702039

Title: Complete sequencing and characterization of 21,243 full-length human cDNAs.

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 16541075

Title: The finished DNA sequence of human chromosome 12.

PubMed ID: 16541075

DOI: 10.1038/nature04569

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 12738229

Title: Regulation of the PAI-1 promoter by circadian clock components: differential activation by BMAL1 and BMAL2.

PubMed ID: 12738229

DOI: 10.1016/s0022-2828(03)00051-8

PubMed ID: 14672706

Title: A novel autofeedback loop of Dec1 transcription involved in circadian rhythm regulation.

PubMed ID: 14672706

DOI: 10.1016/j.bbrc.2003.11.099

PubMed ID: 28112733

Title: Site-specific mapping of the human SUMO proteome reveals co-modification with phosphorylation.

PubMed ID: 28112733

DOI: 10.1038/nsmb.3366

Sequence Information:

  • Length: 636
  • Mass: 70887
  • Checksum: 972CE2BC5B05B1F3
  • Sequence:
    • MAAEEEAAAG GKVLREENQC IAPVVSSRVS PGTRPTAMGS FSSHMTEFPR KRKGSDSDPS 
QSGIMTEKVV EKLSQNPLTY LLSTRIEISA SSGSRVEDGE HQVKMKAFRE AHSQTEKRRR 
DKMNNLIEEL SAMIPQCNPM ARKLDKLTVL RMAVQHLRSL KGLTNSYVGS NYRPSFLQDN 
ELRHLILKTA EGFLFVVGCE RGKILFVSKS VSKILNYDQA SLTGQSLFDF LHPKDVAKVK 
EQLSSFDISP REKLIDAKTG LQVHSNLHAG RTRVYSGSRR SFFCRIKSCK ISVKEEHGCL 
PNSKKKEHRK FYTIHCTGYL RSWPPNIVGM EEERNSKKDN SNFTCLVAIG RLQPYIVPQN 
SGEINVKPTE FITRFAVNGK FVYVDQRATA ILGYLPQELL GTSCYEYFHQ DDHNNLTDKH 
KAVLQSKEKI LTDSYKFRAK DGSFVTLKSQ WFSFTNPWTK ELEYIVSVNT LVLGHSEPGE 
ASFLPCSSQS SEESSRQSCM SVPGMSTGTV LGAGSIGTDI ANEILDLQRL QSSSYLDDSS 
PTGLMKDTHT VNCRSMSNKE LFPPSPSEMG ELEATRQNQS TVAVHSHEPL LSDGAQLDFD 
ALCDNDDTAM AAFMNYLEAE GGLGDPGDFS DIQWTL