Editing Tumor necrosis factor (section)

== Gene ==
=== Location ===
The human TNF [[gene]] is mapped to [[chromosome 6]]p21.3, residing in the [[MHC class III|class III]] region of the [[major histocompatibility complex]], where many immune system genes are contained. The class III region is sandwiched between the [[HLA-DR]] locus on the centromeric side, and the [[HLA-B]] locus on the telomeric side. The TNF gene is 250 kilobases away from the HLA-B locus, and 850 kilobases away from the HLA-DR locus. The TNF gene is located 1,100 kilobases downstream of the [[lymphotoxin alpha|lymphotoxin-α]] gene.<ref name="pmid11040201">{{cite journal | vauthors = Papadakis KA, Targan SR | title = Tumor necrosis factor: biology and therapeutic inhibitors | journal = Gastroenterology | volume = 119 | issue = 4 | pages = 1148–1157 | date = October 2000 | pmid = 11040201 | doi = 10.1053/gast.2000.18160 | doi-access = free }}</ref>

=== Expression ===
[[File:Enhanceosome composition of human TNF.svg|thumb|upright=1.5|class=skin-invert-image|Enhanceosome composition for human TNF for example cell types and stimulants.<ref name="TNFPathophysiology"/>|alt=diagram of enhanceosome composition for example cell types and stimulants]]

TNF is produced rapidly in response to many stimuli by multiple cell types. Cell types that express TNF include [[T cells]], [[B cells]], [[macrophages]], [[mast cells]], [[dendritic cells]], and [[fibroblasts]], and stimuli that activate the TNF gene include pathogenic substances, cytokines from other immune cells, and environment stressors. A few such cytokines include [[interleukin-1]], [[interleukin-2]], [[interferon-γ]], and TNF itself. TNF transcription is activated by a variety of signaling pathways and transcription factors, depending on the cell type and stimulus. TNF transcription does not depend on the synthesis of new proteins, enabling rapid activation of the gene.<ref name="TNFPathophysiology">{{cite book | vauthors = Falvo JV, Tsytsykova AV, Goldfeld AE | title = TNF Pathophysiology | chapter = Transcriptional control of the TNF gene | series = Current Directions in Autoimmunity | volume = 11 | pages = 27–60 | date = 2010 | pmid = 20173386 | pmc = 4785889 | doi = 10.1159/000289196 | publisher = Karger | isbn = 978-3-8055-9384-7 }}</ref>

TNF gene expression is regulated by a proximal promoter region consisting of approximately 200 base pairs. Most of the binding sites within the proximal promoter region can recognize multiple transcription factors, enabling TNF to be activated by a variety of signaling pathways. As transcription factors bind to the promoter region, they also bind to coactivators, assembling into a large structure known as an [[enhanceosome]]. The composition of the enhanceosome depends on ambient factors within the cell, particularly [[nuclear factor of activated T-cells]] (NFAT).<ref name="TNFPathophysiology"/>

TNF expression is also regulated by DNA structure. DNA is coiled around [[histones]], which is loosened by [[Histone acetylation and deacetylation|acetylation]] and condensed by [[Histone methylation|methylation]]. Proteins that acetylate histones at the TNF promoter, particularly [[CREB-binding protein]] in T cells, are often critical for TNF expression. In contrast, several cell types that do not express TNF are highly methylated at the histones of the TNF promoter. Long-range intrachromosomal interactions can also regulate TNF expression. In activated T-cells, the DNA surrounding the TNF promoter circularizes, bringing promoter complexes closer together and enhancing transcription efficiency.<ref name="TNFPathophysiology"/>

=== Transcription ===
[[File:TNF Exons and Introns.svg|thumb|upright=1.5|class=skin-invert-image|Map of human TNF exons and introns.<ref name="pmid2995927">{{cite journal | vauthors = Nedwin GE, Naylor SL, Sakaguchi AY, Smith D, Jarrett-Nedwin J, Pennica D, Goeddel DV, Gray PW | title = Human lymphotoxin and tumor necrosis factor genes: structure, homology and chromosomal localization | journal = Nucleic Acids Research | volume = 13 | issue = 17 | pages = 6361–6373 | date = September 1985 | pmid = 2995927 | pmc = 321958 | doi = 10.1093/nar/13.17.6361 }}</ref>|alt=Diagram of human TNF exons and introns]]
The transcribed region contains 4 [[exons]] separated by 3 [[introns]], for a total of 2,762 base pairs in the [[primary transcript]] and 1,669 base pairs in the mRNA.<ref name="TNFAtlasGeneticsOncology">{{cite journal | vauthors = Chen F | title = TNF (tumor necrosis factor (TNF superfamily, member 2)) | journal = Atlas of Genetics and Cytogenetics in Oncology and Haematology | date = June 2004 |url=https://atlasgeneticsoncology.org/gene/319/tnf-(tumor-necrosis-factor-(tnf-superfamily-member-2)) }}</ref> The mRNA consists of four regions: the [[Five prime untranslated region|5' untranslated region]], which is not included in the TNF protein; the transmembrane portion, which is present in transmembrane TNF but not in soluble TNF; the soluble portion; and the [[Three prime untranslated region|3' untranslated region]]. More than 80% of the soluble portion is contained in the last exon, while the transmembrane portion is contained in the first two exons. The 3' untranslated region contains an [[AU-rich element]] (ARE) that regulates the translation of TNF.<ref name="pmid21133840">{{cite journal | vauthors = Parameswaran N, Patial S | title = Tumor Necrosis Factor-α Signaling in Macrophages | journal =  Critical Reviews in Eukaryotic Gene Expression| volume = 20 | issue = 2 | pages = 87–103 |year = 2010 | doi = 10.1615/critreveukargeneexpr.v20.i2.10 | pmid = 21133840 | pmc = 3066460 }}</ref> In unstimulated macrophages, various proteins bind to the ARE to destabilize TNF mRNA, suppressing the translation of TNF. Upon activation, TNF translation is unsuppressed.<ref name="TNFARE">{{cite journal | vauthors = Zhang T, Kruys V, Huez G, Gueydan C | title = AU-rich element-mediated translational control: complexity and multiple activities of trans-activating factors | journal = Biochemical Society Transactions | volume = 30 | issue = 6 | pages = 952–958 | date = November 2002 | doi = 10.1042/bst0300952 | pmid = 12440953 }}</ref>