Reviewed, UniProtKB/Swiss-Prot P62805 (H4_HUMAN)

Names and origin

Protein names

Recommended name:
    Histone H4

Gene names

Name:	HIST1H4A
Synonyms:	H4/A, H4FA
AND
Name:	HIST1H4B
Synonyms:	H4/I, H4FI
AND
Name:	HIST1H4C
Synonyms:	H4/G, H4FG
AND
Name:	HIST1H4D
Synonyms:	H4/B, H4FB
AND
Name:	HIST1H4E
Synonyms:	H4/J, H4FJ
AND
Name:	HIST1H4F
Synonyms:	H4/C, H4FC
AND
Name:	HIST1H4H
Synonyms:	H4/H, H4FH
AND
Name:	HIST1H4I
Synonyms:	H4/M, H4FM
AND
Name:	HIST1H4J
Synonyms:	H4/E, H4FE
AND
Name:	HIST1H4K
Synonyms:	H4/D, H4FD
AND
Name:	HIST1H4L
Synonyms:	H4/K, H4FK
AND
Name:	HIST2H4A
Synonyms:	H4/N, H4F2, H4FN, HIST2H4
AND
Name:	HIST2H4B
Synonyms:	H4/O, H4FO
AND
Name:	HIST4H4

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	103 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.
Subunit structure	The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.
Subcellular location	Nucleus.
Post-translational modification	Acetylation at Lys-6, Lys-9, Lys-13 and Lys-17 occurs in coding regions of the genome but not in heterochromatin. Citrullination at Arg-4 by PADI4 impairs methylation. Monomethylation at Arg-4 by PRMT1 favors acetylation at Lys-9 and Lys-13. Demethylation is performed by JMJD6. Monomethylated, dimethylated or trimethylated at Lys-21. Monomethylation is performed by SET8. Trimethylation is performed by SUV420H1 and SUV420H2 and induces gene silencing. Ubiquitinated by the CUL4-DDB-RBX1 complex in response to ultraviolet irradiation. This may weaken the interaction between histones and DNA and facilitate DNA accessibility to repair proteins. Sumoylated, which is associated with transcriptional repression.
Sequence similarities	Belongs to the histone H4 family.
Sequence caution	The sequence AAI28106.1 differs from that shown. Reason: Frameshift at position 3.

Ontologies

Keywords
Cellular component	Chromosomal protein Nucleosome core Nucleus
Coding sequence diversity	Polymorphism
Ligand	DNA-binding
PTM	Acetylation Citrullination Methylation Phosphoprotein Ubl conjugation
Technical term	3D-structure Direct protein sequencing
Gene Ontology (GO)
Biological process	nucleosome assembly Inferred from electronic annotation. Source: InterPro phosphoinositide-mediated signaling Non-traceable author statement. Source: UniProtKB
Cellular component	nucleoplasm Inferred from Experiment. Source: Reactome nucleosome Ref.2 Traceable author statement. Source: UniProtKB
Molecular function	DNA binding Ref.2 Traceable author statement. Source: UniProtKB protein binding Inferred from physical interaction. Source: IntAct
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
HDAC1	Q13547	1	EBI-302023,EBI-301834
HDAC4	P56524	1	EBI-302023,EBI-308629
HDAC5	Q9UQL6	1	EBI-302023,EBI-715576
HDAC6	Q9UBN7	1	EBI-302023,EBI-301697
L3MBTL	Q9Y468	2	EBI-302023,EBI-1265089
PRMT1.1	Q9SU94	1	EBI-302023,EBI-1382731	From a different organism.
PRMT1.2	O82210	1	EBI-302023,EBI-1382526	From a different organism.
SETD8	Q9NQR1	4	EBI-302023,EBI-1268946

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Initiator methionine

1

1

Removed

Chain

2 – 103

102

Histone H4

PRO_0000158320

Regions

DNA binding

17 – 21

5

Amino acid modifications

Modified residue

2

1

N-acetylserine

Modified residue

2

1

Phosphoserine

Modified residue

4

1

Citrulline; alternate

Modified residue

4

1

Omega-N-methylarginine; by PRMT1; alternate

Modified residue

4

1

Symmetric dimethylarginine; by PRMT5; alternate By similarity

Modified residue

6

1

N6-acetyllysine

Modified residue

9

1

N6-acetyllysine

Modified residue

13

1

N6-acetyllysine

Modified residue

17

1

N6-acetyllysine

Modified residue

21

1

N6,N6,N6-trimethyllysine; alternate

Modified residue

21

1

N6,N6-dimethyllysine; alternate

Modified residue

21

1

N6-methyllysine; alternate

Modified residue

48

1

Phosphoserine

Modified residue

52

1

Phosphotyrosine

Modified residue

89

1

Phosphotyrosine

Natural variations

Natural variant

64

1

E → Q in a breast cancer sample; somatic mutation.

VAR_036206

Experimental info

Sequence conflict

71

1

V → A in AAH67496. Ref.14

Sequence conflict

77

1

A → P in CAG46986. Ref.11

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

103

Helix Strand Turn

Details...

Helix

27 – 29

3

Helix

32 – 41

10

Helix

51 – 76

26

Beta strand

80 – 82

3

Helix

84 – 93

10

Beta strand

97 – 101

5

Sequences

	Sequence		Length	Mass (Da)
	P62805-1 [UniParc]. Last modified January 23, 2007. Version 2. Checksum: A9E5DFD3F8B97598	FASTA	103	11,367
	10 20 30 40 50 60 MSGRGKGGKG LGKGGAKRHR KVLRDNIQGI TKPAIRRLAR RGGVKRISGL IYEETRGVLK 70 80 90 100 VFLENVIRDA VTYTEHAKRK TVTAMDVVYA LKRQGRTLYG FGG

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Structure and in vitro transcription of a human H4 histone gene." Sierra F., Stein G., Stein J. Nucleic Acids Res. 11:7069-7086(1983) [PubMed: 6314274] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[2]	"Protein-DNA interactions in vivo upstream of a cell cycle-regulated human H4 histone gene." Pauli U., Chrysogelos S., Stein G., Stein J., Nick H. Science 236:1308-1311(1987) [PubMed: 3035717] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]	"Isolation and characterization of two human H1 histone genes within clusters of core histone genes." Albig W., Kardalinou E., Drabent B., Zimmer A., Doenecke D. Genomics 10:940-948(1991) [PubMed: 1916825] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]. Tissue: Placenta.
[4]	"Association of histone H4 genes with the mammalian testis-specific H1t histone gene." Drabent B., Kardalinou E., Bode C., Doenecke D. DNA Cell Biol. 14:591-597(1995) [PubMed: 7626218] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[5]	"Characterization of the H1.5 gene completes the set of human H1 subtype genes." Albig W., Meergans T., Doenecke D. Gene 184:141-148(1997) [PubMed: 9031620] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[6]	"The human histone gene cluster at the D6S105 locus." Albig W., Doenecke D. Hum. Genet. 101:284-294(1997) [PubMed: 9439656] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[7]	"Human histone gene organization: nonregular arrangement within a large cluster." Albig W., Kioschis P., Poustka A., Meergans K., Doenecke D. Genomics 40:314-322(1997) [PubMed: 9119399] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[8]	"The human and mouse replication-dependent histone genes." Marzluff W.F., Gongidi P., Woods K.R., Jin J., Maltais L.J. Genomics 80:487-498(2002) [PubMed: 12408966] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] (HIST1H4A; HIST1H4B; HIST1H4C; HIST1H4D; HIST1H4E; HIST1H4F; HIST1H4H; HIST1H4I; HIST1H4J; HIST1H4K; HIST1H4L; HIST2H4A AND HIST4H4).
[9]	"A recurring translocation, t(3;6)(q27;p21), in non-Hodgkin's lymphoma results in replacement of the 5' regulatory region of BCL6 with a novel H4 histone gene." Akasaka T., Miura I., Takahashi N., Akasaka H., Yonetani N., Ohno H., Fukuhara S., Okuma M. Cancer Res. 57:7-12(1997) [PubMed: 8988030] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[10]	"Functional characterization of a human histone gene cluster duplication." Braastad C.D., Hovhannisyan H., van Wijnen A.J., Stein J.L., Stein G.S. Gene 342:35-40(2004) [PubMed: 15527963] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[11]	"Cloning of human full open reading frames in Gateway(TM) system entry vector (pDONR201)." Halleck A., Ebert L., Mkoundinya M., Schick M., Eisenstein S., Neubert P., Kstrang K., Schatten R., Shen B., Henze S., Mar W., Korn B., Zuo D., Hu Y., LaBaer J. Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (HIST1H4F; HIST1H4H AND HIST2H4A).
[12]	"The DNA sequence and analysis of human chromosome 6." Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L., Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R., Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D., Andrews T.D. , Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H., Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J., Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V., Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J., Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E., Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J., French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J., Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C., Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A., Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R., Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A., Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L., Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I., Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y., Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E., Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A., Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W., Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J., Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M., Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I., Rogers J., Beck S. Nature 425:805-811(2003) [PubMed: 14574404] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA] (HIST1H4A; HIST1H4B; HIST1H4C; HIST1H4D; HIST1H4E; HIST1H4F; HIST1H4H; HIST1H4I; HIST1H4J; HIST1H4K AND HIST1H4L).
[13]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[14]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Bone marrow, Brain, Eye, Lung, Pancreas, Placenta and Prostate.
[15]	Bienvenut W.V. Submitted (MAR-2005) to UniProtKB Cited for: PROTEIN SEQUENCE OF 25-36; 47-56; 61-78 AND 81-93, MASS SPECTROMETRY. Tissue: B-cell lymphoma.
[16]	"Histone H4 acetylation distinguishes coding regions of the human genome from heterochromatin in a differentiation-dependent but transcription-independent manner." O'Neill L.P., Turner B.M. EMBO J. 14:3946-3957(1995) [PubMed: 7664735] [Abstract] Cited for: ACETYLATION AT LYS-6; LYS-9; LYS-13 AND LYS-17.
[17]	"A highly basic histone H4 domain bound to the sharply bent region of nucleosomal DNA." Ebralidse K.K., Grachev S.A., Mirzabekov A.D. Nature 331:365-367(1988) [PubMed: 3340182] [Abstract] Cited for: DNA-BINDING REGION.
[18]	"Histone H4 acetylation in human cells. Frequency of acetylation at different sites defined by immunolabeling with site-specific antibodies." Turner B.M., O'Neill L.P., Allan I.M. FEBS Lett. 253:141-145(1989) [PubMed: 2474456] [Abstract] Cited for: ACETYLATION AT LYS-6; LYS-9; LYS-13 AND LYS-17.
[19]	"Methylation of histone H4 at arginine 3 occurs in vivo and is mediated by the nuclear receptor coactivator PRMT1." Strahl B.D., Briggs S.D., Brame C.J., Caldwell J.A., Koh S.S., Ma H., Cook R.G., Shabanowitz J., Hunt D.F., Stallcup M.R., Allis C.D. Curr. Biol. 11:996-1000(2001) [PubMed: 11448779] [Abstract] Cited for: METHYLATION AT ARG-4.
[20]	"Methylation of histone H4 at arginine 3 facilitating transcriptional activation by nuclear hormone receptor." Wang H., Huang Z.-Q., Xia L., Feng Q., Erdjument-Bromage H., Strahl B.D., Briggs S.D., Allis C.D., Wong J., Tempst P., Zhang Y. Science 293:853-857(2001) [PubMed: 11387442] [Abstract] Cited for: METHYLATION AT ARG-4.
[21]	"PR-Set7 is a nucleosome-specific methyltransferase that modifies lysine 20 of histone H4 and is associated with silent chromatin." Nishioka K., Rice J.C., Sarma K., Erdjument-Bromage H., Werner J., Wang Y., Chuikov S., Valenzuela P., Tempst P., Steward R., Lis J.T., Allis C.D., Reinberg D. Mol. Cell 9:1201-1213(2002) [PubMed: 12086618] [Abstract] Cited for: METHYLATION AT LYS-21.
[22]	"Histone sumoylation is associated with transcriptional repression." Shiio Y., Eisenman R.N. Proc. Natl. Acad. Sci. U.S.A. 100:13225-13230(2003) [PubMed: 14578449] [Abstract] Cited for: SUMOYLATION.
[23]	"Identifying and quantifying in vivo methylation sites by heavy methyl SILAC." Ong S.E., Mittler G., Mann M. Nat. Methods 1:119-126(2004) [PubMed: 15782174] [Abstract] Cited for: METHYLATION [LARGE SCALE ANALYSIS] AT LYS-21, MASS SPECTROMETRY.
[24]	"Human PAD4 regulates histone arginine methylation levels via demethylimination." Wang Y., Wysocka J., Sayegh J., Lee Y.-H., Perlin J.R., Leonelli L., Sonbuchner L.S., McDonald C.H., Cook R.G., Dou Y., Roeder R.G., Clarke S., Stallcup M.R., Allis C.D., Coonrod S.A. Science 306:279-283(2004) [PubMed: 15345777] [Abstract] Cited for: CITRULLINATION AT ARG-4, METHYLATION AT ARG-4.
[25]	"SET8 recognizes the sequence RHRK20VLRDN within the N terminus of histone H4 and mono-methylates lysine 20." Yin Y., Liu C., Tsai S.N., Zhou B., Ngai S.M., Zhu G. J. Biol. Chem. 280:30025-30031(2005) [PubMed: 15964846] [Abstract] Cited for: METHYLATION AT LYS-21.
[26]	"Global, in vivo, and site-specific phosphorylation dynamics in signaling networks." Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M. Cell 127:635-648(2006) [PubMed: 17081983] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-48, MASS SPECTROMETRY. Tissue: Epithelium.
[27]	"Histone H3 and H4 ubiquitylation by the CUL4-DDB-ROC1 ubiquitin ligase facilitates cellular response to DNA damage." Wang H., Zhai L., Xu J., Joo H.-Y., Jackson S., Erdjument-Bromage H., Tempst P., Xiong Y., Zhang Y. Mol. Cell 22:383-394(2006) [PubMed: 16678110] [Abstract] Cited for: UBIQUITINATION.
[28]	"Substrate and functional diversity of lysine acetylation revealed by a proteomics survey." Kim S.C., Sprung R., Chen Y., Xu Y., Ball H., Pei J., Cheng T., Kho Y., Xiao H., Xiao L., Grishin N.V., White M., Yang X.-J., Zhao Y. Mol. Cell 23:607-618(2006) [PubMed: 16916647] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-6; LYS-9; LYS-13 AND LYS-17, MASS SPECTROMETRY. Tissue: Epithelium.
[29]	"Characterization of histones H2A and H2B variants and their post-translational modifications by mass spectrometry." Bonenfant D., Coulot M., Towbin H., Schindler P., van Oostrum J. Mol. Cell. Proteomics 5:541-552(2006) [PubMed: 16319397] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-6; LYS-9 AND LYS-13, METHYLATION AT LYS-21, PHOSPHORYLATION AT SER-2, MASS SPECTROMETRY.
[30]	"Phosphoproteomic analysis of the human pituitary." Beranova-Giorgianni S., Zhao Y., Desiderio D.M., Giorgianni F. Pituitary 9:109-120(2006) [PubMed: 16807684] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-48, MASS SPECTROMETRY. Tissue: Pituitary.
[31]	"Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer." Rikova K., Guo A., Zeng Q., Possemato A., Yu J., Haack H., Nardone J., Lee K., Reeves C., Li Y., Hu Y., Tan Z., Stokes M., Sullivan L., Mitchell J., Wetzel R., Macneill J., Ren J.M. , Yuan J., Bakalarski C.E., Villen J., Kornhauser J.M., Smith B., Li D., Zhou X., Gygi S.P., Gu T.-L., Polakiewicz R.D., Rush J., Comb M.J. Cell 131:1190-1203(2007) [PubMed: 18083107] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-52 AND TYR-89, MASS SPECTROMETRY.
[32]	"Certain and progressive methylation of histone H4 at lysine 20 during the cell cycle." Pesavento J.J., Yang H., Kelleher N.L., Mizzen C.A. Mol. Cell. Biol. 28:468-486(2008) [PubMed: 17967882] [Abstract] Cited for: ACETYLATION AT SER-2; LYS-13 AND LYS-17, PHOSPHORYLATION AT SER-2, METHYLATION AT LYS-21.
[33]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed: 18669648] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-48, MASS SPECTROMETRY.
[34]	"Alteration of the nucleosomal DNA path in the crystal structure of a human nucleosome core particle." Tsunaka Y., Kajimura N., Tate S., Morikawa K. Nucleic Acids Res. 33:3424-3434(2005) [PubMed: 15951514] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS).
[35]	"The consensus coding sequences of human breast and colorectal cancers." Sjoeblom T., Jon