PER3 (period circadian regulator 3)

Gene

• Entrez ID: 8863
• Gene name: Period circadian regulator 3
• Gene symbol: PER3
• Synonyms: FASPS3, GIG13
• Chromosome: 1
• Chromosome location: 1p36.23
• Summary: This gene is a member of the Period family of genes and is expressed in a circadian pattern in the suprachiasmatic nucleus, the primary circadian pacemaker in the mammalian brain. Genes in this family encode components of the circadian rhythms of locomotor activity, metabolism, and behavior. This gene is upregulated by CLOCK/ARNTL heterodimers but then represses this upregulation in a feedback loop using PER/CRY heterodimers to interact with CLOCK/ARNTL. Polymorphisms in this gene have been linked to sleep disorders. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2014]

SNPs

SNP ID	Visualize variation	Clinical significance	Consequence
rs139315125	A>G	Pathogenic	5 prime UTR variant, missense variant, coding sequence variant
rs150812083	C>G	Pathogenic	Missense variant, 5 prime UTR variant, coding sequence variant
rs1558401132	CTTGC>-	Likely-pathogenic	Frameshift variant, 5 prime UTR variant, coding sequence variant

miRNA

miRTarBase ID	miRNA	Experiments	Reference
MIRT029909	hsa-miR-26b-5p	Microarray	19088304
MIRT030960	hsa-miR-21-5p	Microarray	18591254
MIRT440002	hsa-miR-377-3p	HITS-CLIP	24374217
MIRT440003	hsa-miR-154-5p	HITS-CLIP	24374217
MIRT487804	hsa-miR-6763-5p	PAR-CLIP	23592263
MIRT487804	hsa-miR-6763-5p	PAR-CLIP	26701625
MIRT487805	hsa-miR-3150a-3p	PAR-CLIP	23592263
MIRT487805	hsa-miR-3150a-3p	PAR-CLIP	26701625
MIRT487806	hsa-miR-6885-5p	PAR-CLIP	23592263
MIRT487806	hsa-miR-6885-5p	PAR-CLIP	26701625
MIRT487807	hsa-miR-328-5p	PAR-CLIP	23592263
MIRT487807	hsa-miR-328-5p	PAR-CLIP	26701625
MIRT487808	hsa-miR-6825-5p	PAR-CLIP	23592263
MIRT487808	hsa-miR-6825-5p	PAR-CLIP	26701625
MIRT487809	hsa-miR-939-5p	PAR-CLIP	23592263
MIRT487809	hsa-miR-939-5p	PAR-CLIP	26701625
MIRT487810	hsa-miR-1343-5p	PAR-CLIP	23592263
MIRT487810	hsa-miR-1343-5p	PAR-CLIP	26701625
MIRT487811	hsa-miR-8085	PAR-CLIP	23592263
MIRT487811	hsa-miR-8085	PAR-CLIP	26701625
MIRT487812	hsa-miR-3175	PAR-CLIP	23592263
MIRT487812	hsa-miR-3175	PAR-CLIP	26701625
MIRT487813	hsa-miR-6731-5p	PAR-CLIP	23592263
MIRT487813	hsa-miR-6731-5p	PAR-CLIP	26701625
MIRT487814	hsa-miR-4731-5p	PAR-CLIP	23592263
MIRT487814	hsa-miR-4731-5p	PAR-CLIP	26701625
MIRT487815	hsa-miR-4313	PAR-CLIP	23592263
MIRT487815	hsa-miR-4313	PAR-CLIP	26701625
MIRT487816	hsa-miR-1225-3p	PAR-CLIP	23592263
MIRT487816	hsa-miR-1225-3p	PAR-CLIP	26701625
MIRT487817	hsa-miR-8089	PAR-CLIP	23592263
MIRT487817	hsa-miR-8089	PAR-CLIP	26701625
MIRT487818	hsa-miR-4700-5p	PAR-CLIP	23592263
MIRT487818	hsa-miR-4700-5p	PAR-CLIP	26701625
MIRT487819	hsa-miR-4787-5p	PAR-CLIP	23592263
MIRT487819	hsa-miR-4787-5p	PAR-CLIP	26701625
MIRT487820	hsa-miR-4667-5p	PAR-CLIP	23592263
MIRT487820	hsa-miR-4667-5p	PAR-CLIP	26701625
MIRT487821	hsa-miR-6795-3p	PAR-CLIP	23592263
MIRT487821	hsa-miR-6795-3p	PAR-CLIP	26701625
MIRT487822	hsa-miR-3943	PAR-CLIP	23592263
MIRT487822	hsa-miR-3943	PAR-CLIP	26701625
MIRT487823	hsa-miR-320e	PAR-CLIP	23592263

Transcription factors

Transcription factor	Regulation	Reference
ARNTL	Activation	22750052
CLOCK	Activation	22750052

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0000122	Process	Negative regulation of transcription by RNA polymerase II	IBA	21873635
GO:0000122	Process	Negative regulation of transcription by RNA polymerase II	IDA	26903630
GO:0000976	Function	Transcription regulatory region sequence-specific DNA binding	IBA	21873635
GO:0001222	Function	Transcription corepressor binding	IBA	21873635
GO:0005515	Function	Protein binding	IPI	21070773
GO:0005634	Component	Nucleus	IBA	21873635
GO:0005634	Component	Nucleus	IDA	26903630
GO:0005737	Component	Cytoplasm	IBA	21873635
GO:0005737	Component	Cytoplasm	IDA	26903630
GO:0032922	Process	Circadian regulation of gene expression	IBA	21873635
GO:0043153	Process	Entrainment of circadian clock by photoperiod	IBA	21873635
GO:0045187	Process	Regulation of circadian sleep/wake cycle, sleep	IMP	17346965, 19716732, 24439663, 24577121, 26903630
GO:0050821	Process	Protein stabilization	IMP	26903630

Other IDs

• MIM: 603427
• HGNC: 8847
• e!Ensembl: ENSG00000049246

Protein

• UniProt ID: P56645
• Protein name: Period circadian protein homolog 3 (hPER3) (Cell growth-inhibiting gene 13 protein) (Circadian clock protein PERIOD 3)
• Protein function: Originally described as a core component of the circadian clock. The circadian clock, an internal time-keeping system, regulates various physiological processes through the generation of approximately 24 hour circadian rhythms in gene expression, which are translated into rhythms in metabolism and behavior. It is derived from the Latin roots 'circa' (about) and 'diem' (day) and acts as an important regulator of a wide array of physiological functions including metabolism, sleep, body temperature, blood pressure, endocrine, immune, cardiovascular, and renal function. Consists of two major components: the central clock, residing in the suprachiasmatic nucleus (SCN) of the brain, and the peripheral clocks that are present in nearly every tissue and organ system. Both the central and peripheral clocks can be reset by environmental cues, also known as Zeitgebers (German for 'timegivers'). The predominant Zeitgeber for the central clock is light, which is sensed by retina and signals directly to the SCN. The central clock entrains the peripheral clocks through neuronal and hormonal signals, body temperature and feeding-related cues, aligning all clocks with the external light/dark cycle. Circadian rhythms allow an organism to achieve temporal homeostasis with its environment at the molecular level by regulating gene expression to create a peak of protein expression once every 24 hours to control when a particular physiological process is most active with respect to the solar day. Transcription and translation of core clock components (CLOCK, NPAS2, ARNTL/BMAL1, ARNTL2/BMAL2, PER1, PER2, PER3, CRY1 and CRY2) plays a critical role in rhythm generation, whereas delays imposed by post-translational modifications (PTMs) are important for determining the period (tau) of the rhythms (tau refers to the period of a rhythm and is the length, in time, of one complete cycle). A diurnal rhythm is synchronized with the day/night cycle, while the ultradian and infradian rhythms have a period shorter and longer than 24 hours, respectively. Disruptions in the circadian rhythms contribute to the pathology of cardiovascular diseases, cancer, metabolic syndromes and aging. A transcription/translation feedback loop (TTFL) forms the core of the molecular circadian clock mechanism. Transcription factors, CLOCK or NPAS2 and ARNTL/BMAL1 or ARNTL2/BMAL2, form the positive limb of the feedback loop, act in the form of a heterodimer and activate the transcription of core clock genes and clock-controlled genes (involved in key metabolic processes), harboring E-box elements (5'-CACGTG-3') within their promoters. The core clock genes: PER1/2/3 and CRY1/2 which are transcriptional repressors form the negative limb of the feedback loop and interact with the CLOCK|NPAS2-ARNTL/BMAL1|ARNTL2/BMAL2 heterodimer inhibiting its activity and thereby negatively regulating their own expression. This heterodimer also activates nuclear receptors NR1D1, NR1D2, RORA, RORB and RORG, which form a second feedback loop and which activate and repress ARNTL/BMAL1 transcription, respectively. Has a redundant role with the other PER proteins PER1 and PER2 and is not essential for the circadian rhythms maintenance. In contrast, plays an important role in sleep-wake timing and sleep homeostasis probably through the transcriptional regulation of sleep homeostasis-related genes, without influencing circadian parameters. Can bind heme.
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF08447	PAS_3	284 → 374	PAS fold	Domain
  PF12114	Period_C	1029 → 1195	Period protein 2/3C-terminal region	Family

• Sequence:

  MPRGEAPGPGRRGAKDEALGEESGERWSPEFHLQRKLADSSHSEQQDRNRVSEELIMVVQ
  EMKKYFPSERRNKPSTLDALNYALRCVHSVQANSEFFQILSQNGAPQADVSMYSLEELAT
  IASEHTSKNTDTFVAVFSFLSGRLVHISEQAALILNRKKDVLASSHFVDLLAPQDMRVFY
  AHTARAQLPFWNNWTQRAARYECAPVKPFFCRIRGGEDRKQEKCHSPFRIIPYLIHVHHP
  AQPELESEPCCLTVVEKIHSGYEAPRIPVNKRIFTTTHTPGCVFLEVDEKAVPLLGYLPQ
  DLIGTSILSYLHPEDRSLMVAIHQKVLKYAGHPPFEHSPIRFCTQNGDYIILDSSWSSFV
  NPWSRKISFIIGRHKVRTSPLNEDVFATKIKKMNDNDKDITELQEQIYKLLLQPVHVSVS
  SGYGSLGSSGSQEQLVSIASSSEASGHRVEETKAEQMTLQQVYASVNKIKNLGQQLYIES
  MTKSSFKPVTGTRTEPNGGGECKTFTSFHQTLKNNSVYTEPCEDLRNDEHSPSYQQINCI
  DSVIRYLKSYNIPALKRKCISCTNTTSSSSEEDKQNHKADDVQALQAGLQIPAIPKSEMP
  TNGRSIDTGGGAPQILSTAMLSLGSGISQCGYSSTIVHVPPPETARDATLFCEPWTLNMQ
  PAPLTSEEFKHVGLTAAVLSAHTQKEEQNYVDKFREKILSSPYSSYLQQESRSKAKYSYF
  QGDSTSKQTRSAGCRKGKHKRKKLPEPPDSSSSNTGSGPRRGAHQNAQPCCPSAASSPHT
  SSPTFPPAAMVPSQAPYLVPAFPLPAATSPGREYAAPGTAPEGLHGLPLSEGLQPYPAFP
  FPYLDTFMTVFLPDPPVCPLLSPSFLPCPFLGATASSAISPSMSSAMSPTLDPPPSVTSQ
  RREEEKWEAQSEGHPFITSRSSSPLQLNLLQEEMPRPSESPDQMRRNTCPQTEYCVTGNN
  GSESSPATTGALSTGSPPRENPSHPTASALSTGSPPMKNPSHPTASALSTGSPPMKNPSH
  PTASTLSMGLPPSRTPSHPTATVLSTGSPPSESPSRTGSAASGSSDSSIYLTSSVYSSKI
  SQNGQQSQDVQKKETFPNVAEEPIWRMIRQTPERILMTYQVPERVKEVVLKEDLEKLESM
  RQQQPQFSHGQKEELAKVYNWIQSQTVTQEIDIQACVTCENEDSADGAATSCGQVLVEDS
  C

• Sequence length: 1201

Pathways

KEGG:

Circadian rhythm
Circadian entrainment

Associated diseases

Disease name	Disease term	References
	Familial advanced sleep-phase syndrome
	Advanced Sleep-Phase Syndrome, Familial	26903630
	Bipolar Disorder	24150227, 24389266, 21316201, 21835597, 24673294
	Malignant neoplasm of breast	20625127
	Mammary Neoplasms, Human	20625127
	Mammary Neoplasms	20625127
	Breast Carcinoma	20625127
	Crohn Disease	21102463
	Mammary Carcinoma, Human	20625127
	Mental Depression	19708722, 19926609
	Depressive disorder	19708722, 19926609
	Myeloid Leukemia, Chronic	16999817
	Seasonal Affective Disorder	21835597, 17969870
	ADVANCED SLEEP PHASE SYNDROME, FAMILIAL, 3