CTCF

CTCF

Transcriptional repressor CTCF also known as 11-zinc finger protein or CCCTC-binding factor is a transcription factor that in humans is encoded by the CTCF gene.[1][2] CTCF is involved in many cellular processes, including transcriptional regulation, insulator activity, V(D)J recombination[3] and regulation of chromatin architecture.[4]

Discovery

CCCTC-Binding factor or CTCF was initially discovered as a negative regulator of the chicken c-myc gene. This protein was found to be binding to three regularly spaced repeats of the core sequence CCCTC and thus was named CCCTC binding factor.[5]

Function

The primary role of CTCF is thought to be in regulating the 3D structure of chromatin.[4] CTCF binds together strands of DNA, thus forming chromatin loops, and anchors DNA to cellular structures like the nuclear lamina.[6] It also defines the boundaries between active and heterochromatic DNA.

Since the 3D structure of DNA influences the regulation of genes, CTCF's activity influences the expression of genes. CTCF is thought to be a primary part of the activity of insulators, sequences that block the interaction between enhancers and promoters. CTCF binding has also been both shown to promote and repress gene expression. It is unknown whether CTCF affects gene expression solely through its looping activity, or if it has some other, unknown, activity.[4]

Observed activity

The binding of CTCF has been shown to have many effects, which are enumerated below. In each case, it is unknown if CTCF directly evokes the outcome or if it does so indirectly (in particular through its looping role).

Transcriptional regulation

The protein CTCF plays a heavy role in repressing the insulin-like growth factor 2 gene, by binding to the H-19 imprinting control region (ICR) along with differentially-methylated region-1 (DMR1) and MAR3.[7][8]

Insulation

Binding of targeting sequence elements by CTCF can block the interaction between enhancers and promoters, therefore limiting the activity of enhancers to certain functional domains. Besides acting as enhancer blocking, CTCF can also act as a chromatin barrier[9] by preventing the spread of heterochromatin structures.

Regulation of chromatin architecture

CTCF physically binds to itself to form homodimers,[10] which causes the bound DNA to form loops.[11] CTCF also occurs frequently at the boundaries of sections of DNA bound to the nuclear lamina.[6] Using chromatin immuno-precipitation (ChIP) followed by ChIP-seq, it was found that CTCF localizes with cohesin genome-wide and affects gene regulatory mechanisms and the higher-order chromatin structure.[12]

Regulation of RNA splicing

CTCF binding has been shown to influence mRNA splicing.[13]

DNA binding

CTCF binds to the consensus sequence CCGCGNGGNGGCAG (in IUPAC notation).[14] This sequence is defined by 11 zinc finger motifs in its structure. CTCF's binding is disrupted by CpG methylation of the DNA it binds to.[15]

CTCF binds to an average of about 55,000 DNA sites in 19 diverse cell types (12 normal and 7 immortal) and in total 77,811 distinct binding sites across all 19 cell types.[16] CTCF’s ability to bind to multiple sequences through the usage of various combinations of its zinc fingers earned it the status of a “multivalent protein”.[1] More than 30,000 CTCF binding sites have been characterized.[17] The human genome contains anywhere between 15,000-40,000 CTCF binding sites depending on cell type, suggesting a widespread role for CTCF in gene regulation.[9][14][18] In addition CTCF binding sites act as nucleosome positioning anchors so that, when used to align various genomic signals, multiple flanking nucleosomes can be readily identified.[9][19] On the other hand, high-resolution nucleosome mapping studies have demonstrated that the differences of CTCF binding between cell types may be attributed to the differences in nucleosome locations.[20]

Protein-protein interactions

CTCF binds to itself to form homodimers.[10] This activity is one possibility of the mechanism of its looping activity.

CTCF has also been shown to [22]

References


-- Module:Hatnote -- -- -- -- This module produces hatnote links and links to related articles. It -- -- implements the and meta-templates and includes -- -- helper functions for other Lua hatnote modules. --


local libraryUtil = require('libraryUtil') local checkType = libraryUtil.checkType local mArguments -- lazily initialise Module:Arguments local yesno -- lazily initialise Module:Yesno

local p = {}


-- Helper functions


local function getArgs(frame) -- Fetches the arguments from the parent frame. Whitespace is trimmed and -- blanks are removed. mArguments = require('Module:Arguments') return mArguments.getArgs(frame, {parentOnly = true}) end

local function removeInitialColon(s) -- Removes the initial colon from a string, if present. return s:match('^:?(.*)') end

function p.findNamespaceId(link, removeColon) -- Finds the namespace id (namespace number) of a link or a pagename. This -- function will not work if the link is enclosed in double brackets. Colons -- are trimmed from the start of the link by default. To skip colon -- trimming, set the removeColon parameter to true. checkType('findNamespaceId', 1, link, 'string') checkType('findNamespaceId', 2, removeColon, 'boolean', true) if removeColon ~= false then link = removeInitialColon(link) end local namespace = link:match('^(.-):') if namespace then local nsTable = mw.site.namespaces[namespace] if nsTable then return nsTable.id end end return 0 end

function p.formatPages(...) -- Formats a list of pages using formatLink and returns it as an array. Nil -- values are not allowed. local pages = {...} local ret = {} for i, page in ipairs(pages) do ret[i] = p._formatLink(page) end return ret end

function p.formatPageTables(...) -- Takes a list of page/display tables and returns it as a list of -- formatted links. Nil values are not allowed. local pages = {...} local links = {} for i, t in ipairs(pages) do checkType('formatPageTables', i, t, 'table') local link = t[1] local display = t[2] links[i] = p._formatLink(link, display) end return links end

function p.makeWikitextError(msg, helpLink, addTrackingCategory) -- Formats an error message to be returned to wikitext. If -- addTrackingCategory is not false after being returned from -- Module:Yesno, and if we are not on a talk page, a tracking category -- is added. checkType('makeWikitextError', 1, msg, 'string') checkType('makeWikitextError', 2, helpLink, 'string', true) yesno = require('Module:Yesno') local title = mw.title.getCurrentTitle() -- Make the help link text. local helpText if helpLink then helpText = ' (help)' else helpText = end -- Make the category text. local category if not title.isTalkPage and yesno(addTrackingCategory) ~= false then category = 'Hatnote templates with errors' category = string.format( '%s:%s', mw.site.namespaces[14].name, category ) else category = end return string.format( '%s', msg, helpText, category ) end


-- Format link -- -- Makes a wikilink from the given link and display values. Links are escaped -- with colons if necessary, and links to sections are detected and displayed -- with " § " as a separator rather than the standard MediaWiki "#". Used in -- the template.


function p.formatLink(frame) local args = getArgs(frame) local link = args[1] local display = args[2] if not link then return p.makeWikitextError( 'no link specified', 'Template:Format hatnote link#Errors', args.category ) end return p._formatLink(link, display) end

function p._formatLink(link, display) -- Find whether we need to use the colon trick or not. We need to use the -- colon trick for categories and files, as otherwise category links -- categorise the page and file links display the file. checkType('_formatLink', 1, link, 'string') checkType('_formatLink', 2, display, 'string', true) link = removeInitialColon(link) local namespace = p.findNamespaceId(link, false) local colon if namespace == 6 or namespace == 14 then colon = ':' else colon = end -- Find whether a faux display value has been added with the | magic -- word. if not display then local prePipe, postPipe = link:match('^(.-)|(.*)$') link = prePipe or link display = postPipe end -- Find the display value. if not display then local page, section = link:match('^(.-)#(.*)$') if page then display = page .. ' § ' .. section end end -- Assemble the link. if display then return string.format('%s', colon, link, display) else return string.format('%s%s', colon, link) end end


-- Hatnote -- -- Produces standard hatnote text. Implements the template.


function p.hatnote(frame) local args = getArgs(frame) local s = args[1] local options = {} if not s then return p.makeWikitextError( 'no text specified', 'Template:Hatnote#Errors', args.category ) end options.extraclasses = args.extraclasses options.selfref = args.selfref return p._hatnote(s, options) end

function p._hatnote(s, options) checkType('_hatnote', 1, s, 'string') checkType('_hatnote', 2, options, 'table', true) local classes = {'hatnote'} local extraclasses = options.extraclasses local selfref = options.selfref if type(extraclasses) == 'string' then classes[#classes + 1] = extraclasses end if selfref then classes[#classes + 1] = 'selfref' end return string.format( '
%s
', table.concat(classes, ' '), s )

end

return p-------------------------------------------------------------------------------- -- Module:Hatnote -- -- -- -- This module produces hatnote links and links to related articles. It -- -- implements the and meta-templates and includes -- -- helper functions for other Lua hatnote modules. --


local libraryUtil = require('libraryUtil') local checkType = libraryUtil.checkType local mArguments -- lazily initialise Module:Arguments local yesno -- lazily initialise Module:Yesno

local p = {}


-- Helper functions


local function getArgs(frame) -- Fetches the arguments from the parent frame. Whitespace is trimmed and -- blanks are removed. mArguments = require('Module:Arguments') return mArguments.getArgs(frame, {parentOnly = true}) end

local function removeInitialColon(s) -- Removes the initial colon from a string, if present. return s:match('^:?(.*)') end

function p.findNamespaceId(link, removeColon) -- Finds the namespace id (namespace number) of a link or a pagename. This -- function will not work if the link is enclosed in double brackets. Colons -- are trimmed from the start of the link by default. To skip colon -- trimming, set the removeColon parameter to true. checkType('findNamespaceId', 1, link, 'string') checkType('findNamespaceId', 2, removeColon, 'boolean', true) if removeColon ~= false then link = removeInitialColon(link) end local namespace = link:match('^(.-):') if namespace then local nsTable = mw.site.namespaces[namespace] if nsTable then return nsTable.id end end return 0 end

function p.formatPages(...) -- Formats a list of pages using formatLink and returns it as an array. Nil -- values are not allowed. local pages = {...} local ret = {} for i, page in ipairs(pages) do ret[i] = p._formatLink(page) end return ret end

function p.formatPageTables(...) -- Takes a list of page/display tables and returns it as a list of -- formatted links. Nil values are not allowed. local pages = {...} local links = {} for i, t in ipairs(pages) do checkType('formatPageTables', i, t, 'table') local link = t[1] local display = t[2] links[i] = p._formatLink(link, display) end return links end

function p.makeWikitextError(msg, helpLink, addTrackingCategory) -- Formats an error message to be returned to wikitext. If -- addTrackingCategory is not false after being returned from -- Module:Yesno, and if we are not on a talk page, a tracking category -- is added. checkType('makeWikitextError', 1, msg, 'string') checkType('makeWikitextError', 2, helpLink, 'string', true) yesno = require('Module:Yesno') local title = mw.title.getCurrentTitle() -- Make the help link text. local helpText if helpLink then helpText = ' (help)' else helpText = end -- Make the category text. local category if not title.isTalkPage and yesno(addTrackingCategory) ~= false then category = 'Hatnote templates with errors' category = string.format( '%s:%s', mw.site.namespaces[14].name, category ) else category = end return string.format( '%s', msg, helpText, category ) end


-- Format link -- -- Makes a wikilink from the given link and display values. Links are escaped -- with colons if necessary, and links to sections are detected and displayed -- with " § " as a separator rather than the standard MediaWiki "#". Used in -- the template.


function p.formatLink(frame) local args = getArgs(frame) local link = args[1] local display = args[2] if not link then return p.makeWikitextError( 'no link specified', 'Template:Format hatnote link#Errors', args.category ) end return p._formatLink(link, display) end

function p._formatLink(link, display) -- Find whether we need to use the colon trick or not. We need to use the -- colon trick for categories and files, as otherwise category links -- categorise the page and file links display the file. checkType('_formatLink', 1, link, 'string') checkType('_formatLink', 2, display, 'string', true) link = removeInitialColon(link) local namespace = p.findNamespaceId(link, false) local colon if namespace == 6 or namespace == 14 then colon = ':' else colon = end -- Find whether a faux display value has been added with the | magic -- word. if not display then local prePipe, postPipe = link:match('^(.-)|(.*)$') link = prePipe or link display = postPipe end -- Find the display value. if not display then local page, section = link:match('^(.-)#(.*)$') if page then display = page .. ' § ' .. section end end -- Assemble the link. if display then return string.format('%s', colon, link, display) else return string.format('%s%s', colon, link) end end


-- Hatnote -- -- Produces standard hatnote text. Implements the template.


function p.hatnote(frame) local args = getArgs(frame) local s = args[1] local options = {} if not s then return p.makeWikitextError( 'no text specified', 'Template:Hatnote#Errors', args.category ) end options.extraclasses = args.extraclasses options.selfref = args.selfref return p._hatnote(s, options) end

function p._hatnote(s, options) checkType('_hatnote', 1, s, 'string') checkType('_hatnote', 2, options, 'table', true) local classes = {'hatnote'} local extraclasses = options.extraclasses local selfref = options.selfref if type(extraclasses) == 'string' then classes[#classes + 1] = extraclasses end if selfref then classes[#classes + 1] = 'selfref' end return string.format( '
%s
', table.concat(classes, ' '), s )

end

return p
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Further reading

External links