Editing Circadian clock (section)

=== Mammalian clocks ===
Selective [[gene knockdown]] of known components of the human circadian clock demonstrates both active compensatory mechanisms and redundancy are used to maintain function of the clock.<ref name="Walton">{{cite journal | vauthors = Walton ZE, Altman BJ, Brooks RC, Dang CV |title=Circadian Clock's Cancer Connections |journal=Annual Review of Cancer Biology |date=4 March 2018 |volume=2 |issue=1 |pages=133–153 |doi=10.1146/annurev-cancerbio-030617-050216 |s2cid=91120424 |language=en |issn=2472-3428|doi-access=free }}</ref><ref name="Zhang">{{cite journal | vauthors = Zhang EE, Liu AC, Hirota T, Miraglia LJ, Welch G, Pongsawakul PY, Liu X, Atwood A, Huss JW, Janes J, Su AI, Hogenesch JB, Kay SA | display-authors = 6 | title = A genome-wide RNAi screen for modifiers of the circadian clock in human cells | journal = Cell | volume = 139 | issue = 1 | pages = 199–210 | date = October 2009 | pmid = 19765810 | pmc = 2777987 | doi = 10.1016/j.cell.2009.08.031 }}</ref><ref name="Baggs">{{cite journal | vauthors = Baggs JE, Price TS, DiTacchio L, Panda S, Fitzgerald GA, Hogenesch JB | title = Network features of the mammalian circadian clock | journal = PLOS Biology | volume = 7 | issue = 3 | pages = e52 | date = March 2009 | pmid = 19278294 | pmc = 2653556 | doi = 10.1371/journal.pbio.1000052 | veditors = Schibler U | doi-access = free }}</ref><ref>{{cite journal | vauthors = Brancaccio M, Edwards MD, Patton AP, Smyllie NJ, Chesham JE, Maywood ES, Hastings MH | title = Cell-autonomous clock of astrocytes drives circadian behavior in mammals | journal = Science | volume = 363 | issue = 6423 | pages = 187–192 | date = January 2019 | pmid = 30630934 | pmc = 6440650 | doi = 10.1126/science.aat4104 | bibcode = 2019Sci...363..187B }}</ref>
Several [[mammalian]] clock genes have been identified and characterized through experiments on animals harboring naturally occurring, chemically induced, and targeted knockout mutations, and various comparative genomic approaches.<ref name="Walton"/>

The majority of identified clock components are transcriptional activators or repressors that modulate protein stability and nuclear translocation and create two interlocking [[feedback loops]].<ref name="Ko">{{cite journal | vauthors = Ko CH, Takahashi JS | title = Molecular components of the mammalian circadian clock | journal = Human Molecular Genetics | volume = 15 | issue = Spec No 2 | pages = R271–R277 | date = October 2006 | pmid = 16987893 | doi = 10.1093/hmg/ddl207 | doi-access = free | pmc = 3762864 }}</ref> In the primary feedback loop, members of the [[basic helix-loop-helix]] (bHLH)-PAS (Period-Arnt-Single-minded) transcription factor family, [[CLOCK]] and [[ARNTL|BMAL1]], [[heterodimer]]ize in the cytoplasm to form a complex that, following translocation to the [[Cell nucleus|nucleus]], initiates transcription of target genes such as the core clock genes 'period' genes ([[PER1]], [[PER2]], and [[PER3]]) and two cryptochrome genes ([[CRY1]] and [[CRY2]]). [[Negative feedback]] is achieved by PER:CRY heterodimers that translocate back to the nucleus to repress their own transcription by inhibiting the activity of the CLOCK:BMAL1 complexes.<ref name="Lowrey"/> Another regulatory loop is induced when CLOCK:BMAL1 heterodimers activate the transcription of [[Rev-ErbA]] and Rora, two retinoic acid-related orphan nuclear receptors. REV-ERBa and RORa subsequently compete to bind Retinoid-related orphan receptor response element|retinoic acid-related orphan receptor response elements (ROREs) present in Bmal1 promoter. Through the subsequent binding of ROREs, members of ROR and REV-ERB are able to regulate ''Bmal1''. While RORs activate transcription of ''Bmal1'', REV-ERBs repress the same transcription process. Hence, the circadian oscillation of ''Bmal1'' is both positively and negatively regulated by RORs and REV-ERBs.<ref name="Ko"/>