Chapter 30 : Genome-Wide Approaches to Defining Macrophage Identity and Function

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Preview this chapter:
Zoom in

Genome-Wide Approaches to Defining Macrophage Identity and Function, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555819194/9781555819187_Chap30-1.gif /docserver/preview/fulltext/10.1128/9781555819194/9781555819187_Chap30-2.gif


Macrophages are among the most phenotypically diverse cell types of mammalian organisms ( ). They inhabit all or nearly all tissues under healthy conditions, where they play important roles as sentinels of infection and injury. These functions are enabled by the expression of a multitude of cell surface and internal receptors that recognize microbial-associated molecular patterns and/or damage-associated molecular patterns, exemplified by Toll-like receptors (TLRs) ( ). Engagement of these receptors by microbial components, such as bacterial lipopolysaccharide (LPS), initiates signaling cascades that lead to the activation of latent transcription factors, including NF-κB, interferon regulatory factors (IRFs), and members of the activator protein 1 (AP1) family ( ). These factors, in turn, function to activate hundreds of genes that play key roles in the orchestration of the innate immune response and that influence the development of adaptive immunity ( ). In addition to this sentinel function, macrophages are professional phagocytes, serving to clear bacteria, apoptotic cells, and a diverse range of host-derived and environmental debris, thereby contributing to an additional layer of immunity and tissue homeostasis ( ).

Citation: Fonseca G, Seidman J, Glass C. 2017. Genome-Wide Approaches to Defining Macrophage Identity and Function, p 553-570. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0039-2016
Highlighted Text: Show | Hide
Loading full text...

Full text loading...


Image of Figure 1
Figure 1

General organization of enhancers and promoters. DNA is packaged into nucleosomes that are displaced by sequence-specific transcription factors and coactivators. Promoters are primarily occupied by broadly expressed transcription factors, whereas enhancers are enriched for the binding of LDTFs. SDTFs can bind to enhancers or promoters (here shown only at the enhancer). Promoters are distinguished by high levels of H3K4me3 compared to H3K4me1 and H3K4me2. Enhancers are characterized by high levels of H3K4me1 relative to H3K4me3. Active enhancers and promoters are associated with transcriptional coactivators and acetylated histones, such as H3K27ac. Active enhancers are frequently associated with RNA polymerase II (Pol II) enzymes that generate eRNAs.

Citation: Fonseca G, Seidman J, Glass C. 2017. Genome-Wide Approaches to Defining Macrophage Identity and Function, p 553-570. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0039-2016
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 2
Figure 2

Superenhancers (SEs) in macrophages. (A) Venn diagram of shared and subset-specific superenhancers in thioglycolate-elicited macrophages (TGEMs), large peritoneal macrophages (LPMs), and microglia. (B) Examples of subset-specific superenhancers near the and genes in TGEMs, LPMs, and microglia. (C) Partial listing of the 151 genes associated with superenhancers found in all three macrophage subsets. (D) Partial listing of genes associated with the 257 superenhancers selectively found in microglia.

Citation: Fonseca G, Seidman J, Glass C. 2017. Genome-Wide Approaches to Defining Macrophage Identity and Function, p 553-570. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0039-2016
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 3
Figure 3

A collaborative/hierarchical model for selection and activation of macrophage enhancers. Macrophage LDTFs, exemplified by PU.1 and C/EBPs, collaborate with each other to bind to genomic regions containing closely spaced PU.1 and C/EBP recognition motifs to establish a primed enhancer. Signal-dependent activation of NF-κB (here shown as p50 and p65) leads to its binding to primed enhancers and enhancer activation, resulting in histone acetylation and production of eRNAs.

Citation: Fonseca G, Seidman J, Glass C. 2017. Genome-Wide Approaches to Defining Macrophage Identity and Function, p 553-570. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0039-2016
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 4
Figure 4

Selection and activation of tissue-specific macrophage enhancers. (A) Generic model. A core set of macrophage LDTFs, exemplified by PU.1 and C/EBP factors, prime a common set of enhancers in many or all macrophage subsets. These enhancers can be acted upon by environment-specific signals to drive the expression of direct target genes. A subset of these genes includes transcription factors that can collaborate with macrophage LDTFs, such as PU.1, to select a secondary, tissue-specific set of enhancers that drive expression of additional target genes. The tissue-specific gene expression program thus results from both direct and indirect environmental effects. (B) Examples of signals preferential for the peritoneal cavity (retinoic acid) or brain (TGF-β), resulting in expression of collaborative factors Gata6 or SMADs, respectively. MG, microglia.

Citation: Fonseca G, Seidman J, Glass C. 2017. Genome-Wide Approaches to Defining Macrophage Identity and Function, p 553-570. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0039-2016
Permissions and Reprints Request Permissions
Download as Powerpoint


1. Gordon S,, Plüddemann A,, Martinez Estrada F . 2014. Macrophage heterogeneity in tissues: phenotypic diversity and functions. Immunol Rev 262 : 36 55.[PubMed] [CrossRef]
2. Wynn TA,, Chawla A,, Pollard JW . 2013. Macrophage biology in development, homeostasis and disease. Nature 496 : 445 455.[PubMed] [CrossRef]
3. Barton GM,, Medzhitov R . 2002. Toll-like receptors and their ligands. Curr Top Microbiol Immunol 270 : 81 92.[PubMed] [CrossRef]
4. Medzhitov R,, Horng T . 2009. Transcriptional control of the inflammatory response. Nat Rev Immunol 9 : 692 703.[PubMed] [CrossRef]
5. Smale ST . 2012. Transcriptional regulation in the innate immune system. Curr Opin Immunol 24 : 51 57.[PubMed] [CrossRef]
6. Pasare C,, Medzhitov R . 2005. Toll-like receptors: linking innate and adaptive immunity. Adv Exp Med Biol 560 : 11 18.[PubMed] [CrossRef]
7. Glass CK,, Natoli G . 2016. Molecular control of activation and priming in macrophages. Nat Immunol 17 : 26 33.[PubMed] [CrossRef]
8. Hong S,, Dissing-Olesen L,, Stevens B . 2016. New insights on the role of microglia in synaptic pruning in health and disease. Curr Opin Neurobiol 36 : 128 134.[PubMed] [CrossRef]
9. Lumeng CN . 2016. Lung macrophage diversity and asthma. Ann Am Thorac Soc 13( Suppl 1) : S31 S34. doi:10.1513/AnnalsATS.201506-384MG. [PubMed]
10. Kurotaki D,, Uede T,, Tamura T . 2015. Functions and development of red pulp macrophages. Microbiol Immunol 59 : 55 62.[PubMed] [CrossRef]
11. Tabas I,, Bornfeldt KE . 2016. Macrophage phenotype and function in different stages of atherosclerosis. Circ Res 118 : 653 667.[PubMed] [CrossRef]
12. Olefsky JM,, Glass CK . 2010. Macrophages, inflammation, and insulin resistance. Annu Rev Physiol 72 : 219 246.[PubMed] [CrossRef]
13. Ju C,, Mandrekar P . 2015. Macrophages and alcohol-related liver inflammation. Alcohol Res 37 : 251 262.[PubMed]
14. Huang W,, Metlakunta A,, Dedousis N,, Zhang P,, Sipula I,, Dube JJ,, Scott DK,, O’Doherty RM . 2010. Depletion of liver Kupffer cells prevents the development of diet-induced hepatic steatosis and insulin resistance. Diabetes 59 : 347 357.[PubMed] [CrossRef]
15. Ransohoff RM,, El Khoury J . 2015. Microglia in health and disease. Cold Spring Harb Perspect Biol 8 : a020560. doi:10.1101/cshperspect.a020560. [PubMed]
16. Villegas-Llerena C,, Phillips A,, Garcia-Reitboeck P,, Hardy J,, Pocock JM . 2016. Microglial genes regulating neuroinflammation in the progression of Alzheimer’s disease. Curr Opin Neurobiol 36 : 74 81.[PubMed] [CrossRef]
17. Noy R,, Pollard JW . 2014. Tumor-associated macrophages: from mechanisms to therapy. Immunity 41 : 49 61.[PubMed] [CrossRef]
18. De Vlaeminck Y,, González-Rascón A,, Goyvaerts C,, Breckpot K . 2016. Cancer-associated myeloid regulatory cells. Front Immunol 7 : 113. [PubMed] [CrossRef]
19. Winter DR,, Jung S,, Amit I . 2015. Making the case for chromatin profiling: a new tool to investigate the immune-regulatory landscape. Nat Rev Immunol 15 : 585 594.[PubMed] [CrossRef]
20. Pennacchio LA,, Ahituv N,, Moses AM,, Prabhakar S,, Nobrega MA,, Shoukry M,, Minovitsky S,, Dubchak I,, Holt A,, Lewis KD,, Plajzer-Frick I,, Akiyama J,, De Val S,, Afzal V,, Black BL,, Couronne O,, Eisen MB,, Visel A,, Rubin EM . 2006. In vivo enhancer analysis of human conserved non-coding sequences. Nature 444 : 499 502.[PubMed] [CrossRef]
21. Woolfe A,, Goodson M,, Goode DK,, Snell P,, McEwen GK,, Vavouri T,, Smith SF,, North P,, Callaway H,, Kelly K,, Walter K,, Abnizova I,, Gilks W,, Edwards YJ,, Cooke JE,, Elgar G . 2005. Highly conserved non-coding sequences are associated with vertebrate development. PLoS Biol 3 : e7. doi:10.1371/journal.pbio.0030007. [CrossRef]
22. Banerji J,, Rusconi S,, Schaffner W . 1981. Expression of a β-globin gene is enhanced by remote SV40 DNA sequences. Cell 27 : 299 308.[PubMed] [CrossRef]
23. Heinz S,, Romanoski CE,, Benner C,, Glass CK . 2015. The selection and function of cell type-specific enhancers. Nat Rev Mol Cell Biol 16 : 144 154.[PubMed] [CrossRef]
24. Liu Z,, Merkurjev D,, Yang F,, Li W,, Oh S,, Friedman MJ,, Song X,, Zhang F,, Ma Q,, Ohgi KA,, Krones A,, Rosenfeld MG . 2014. Enhancer activation requires trans-recruitment of a mega transcription factor complex. Cell 159 : 358 373.[PubMed] [CrossRef]
25. De Santa F,, Barozzi I,, Mietton F,, Ghisletti S,, Polletti S,, Tusi BK,, Muller H,, Ragoussis J,, Wei CL,, Natoli G . 2010. A large fraction of extragenic RNA Pol II transcription sites overlap enhancers. PLoS Biol 8 : e1000384. doi:10.1371/journal.pbio.1000384. [PubMed] [CrossRef]
26. Heintzman ND,, Stuart RK,, Hon G,, Fu Y,, Ching CW,, Hawkins RD,, Barrera LO,, Van Calcar S,, Qu C,, Ching KA,, Wang W,, Weng Z,, Green RD,, Crawford GE,, Ren B . 2007. Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nat Genet 39 : 311 318.[PubMed] [CrossRef]
27. Creyghton MP,, Cheng AW,, Welstead GG,, Kooistra T,, Carey BW,, Steine EJ,, Hanna J,, Lodato MA,, Frampton GM,, Sharp PA,, Boyer LA,, Young RA,, Jaenisch R . 2010. Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc Natl Acad Sci U S A 107 : 21931 21936.[PubMed] [CrossRef]
28. ENCODE Project Consortium . 2012. An integrated encyclopedia of DNA elements in the human genome. Nature 489 : 5774.[PubMed] [CrossRef]
29. Huang J,, Liu X,, Li D,, Shao Z,, Cao H,, Zhang Y,, Trompouki E,, Bowman TV,, Zon LI,, Yuan GC,, Orkin SH,, Xu J . 2016. Dynamic control of enhancer repertoires drives lineage and stage-specific transcription during hematopoiesis. Dev Cell 36 : 9 23.[PubMed] [CrossRef]
30. Wright AV,, Nuñez JK,, Doudna JA . 2016. Biology and applications of CRISPR systems: harnessing nature’s toolbox for genome engineering. Cell 164 : 29 44.[PubMed] [CrossRef]
31. Lam MTY,, Li W,, Rosenfeld MG,, Glass CK . 2014. Enhancer RNAs and regulated transcriptional programs. Trends Biochem Sci 39 : 170 182.[PubMed] [CrossRef]
32. Li W,, Notani D,, Rosenfeld MG . 2016. Enhancers as non-coding RNA transcription units: recent insights and future perspectives. Nat Rev Genet 17 : 207 223.[PubMed] [CrossRef]
33. Kaikkonen MU,, Spann NJ,, Heinz S,, Romanoski CE,, Allison KA,, Stender JD,, Chun HB,, Tough DF,, Prinjha RK,, Benner C,, Glass CK . 2013. Remodeling of the enhancer landscape during macrophage activation is coupled to enhancer transcription. Mol Cell 51 : 310 325.[PubMed] [CrossRef]
34. Lam MT,, Cho H,, Lesch HP,, Gosselin D,, Heinz S,, Tanaka-Oishi Y,, Benner C,, Kaikkonen MU,, Kim AS,, Kosaka M,, Lee CY,, Watt A,, Grossman TR,, Rosenfeld MG,, Evans RM,, Glass CK . 2013. Rev-Erbs repress macrophage gene expression by inhibiting enhancer-directed transcription. Nature 498 : 511 515.[PubMed] [CrossRef]
35. Li W,, Notani D,, Ma Q,, Tanasa B,, Nunez E,, Chen AY,, Merkurjev D,, Zhang J,, Ohgi K,, Song X,, Oh S,, Kim HS,, Glass CK,, Rosenfeld MG . 2013. Functional roles of enhancer RNAs for oestrogen-dependent transcriptional activation. Nature 498 : 516 520.[PubMed] [CrossRef]
36. Schaukowitch K,, Joo JY,, Liu X,, Watts JK,, Martinez C,, Kim TK . 2014. Enhancer RNA facilitates NELF release from immediate early genes. Mol Cell 56 : 29 42.[PubMed] [CrossRef]
37. Sigova AA,, Abraham BJ,, Ji X,, Molinie B,, Hannett NM,, Guo YE,, Jangi M,, Giallourakis CC,, Sharp PA,, Young RA . 2015. Transcription factor trapping by RNA in gene regulatory elements. Science 350 : 978 981.[PubMed] [CrossRef]
38. Lai F,, Gardini A,, Zhang A,, Shiekhattar R . 2015. Integrator mediates the biogenesis of enhancer RNAs. Nature 525 : 399 403.[PubMed] [CrossRef]
39. Austenaa LM,, Barozzi I,, Simonatto M,, Masella S,, Della Chiara G,, Ghisletti S,, Curina A,, de Wit E,, Bouwman BA,, de Pretis S,, Piccolo V,, Termanini A,, Prosperini E,, Pelizzola M,, de Laat W,, Natoli G . 2015. Transcription of mammalian cis-regulatory elements is restrained by actively enforced early termination. Mol Cell 60 : 460 474.[PubMed] [CrossRef]
40. Hnisz D,, Abraham BJ,, Lee TI,, Lau A,, Saint-André V,, Sigova AA,, Hoke HA,, Young RA . 2013. Super-enhancers in the control of cell identity and disease. Cell 155 : 934 947.[PubMed] [CrossRef]
41. Whyte WA,, Orlando DA,, Hnisz D,, Abraham BJ,, Lin CY,, Kagey MH,, Rahl PB,, Lee TI,, Young RA . 2013. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell 153 : 307 319.[PubMed] [CrossRef]
42. Parker SC,, Stitzel ML,, Taylor DL,, Orozco JM,, Erdos MR,, Akiyama JA,, van Bueren KL,, Chines PS,, Narisu N,, NISC Comparative Sequencing Program, Black BL,, Visel A,, Pennacchio LA,, Collins FS , National Institutes of Health Intramural Sequencing Center Comparative Sequencing Program Authors, NISC Comparative Sequencing Program Authors . 2013. Chromatin stretch enhancer states drive cell-specific gene regulation and harbor human disease risk variants. Proc Natl Acad Sci U S A 110 : 17921 17926.[PubMed] [CrossRef]
43. Hnisz D,, Schuijers J,, Lin CY,, Weintraub AS,, Abraham BJ,, Lee TI,, Bradner JE,, Young RA . 2015. Convergence of developmental and oncogenic signaling pathways at transcriptional super-enhancers. Mol Cell 58 : 362 370.[PubMed] [CrossRef]
44. Hah N,, Benner C,, Chong LW,, Yu RT,, Downes M,, Evans RM . 2015. Inflammation-sensitive super enhancers form domains of coordinately regulated enhancer RNAs. Proc Natl Acad Sci U S A 112 : E297 E302.[PubMed] [CrossRef]
45. Gosselin D,, Link VM,, Romanoski CE,, Fonseca GJ,, Eichenfield DZ,, Spann NJ,, Stender JD,, Chun HB,, Garner H,, Geissmann F,, Glass CK . 2014. Environment drives selection and function of enhancers controlling tissue-specific macrophage identities. Cell 159 : 1327 1340.[PubMed] [CrossRef]
46. Kagey MH,, Newman JJ,, Bilodeau S,, Zhan Y,, Orlando DA,, van Berkum NL,, Ebmeier CC,, Goossens J,, Rahl PB,, Levine SS,, Taatjes DJ,, Dekker J,, Young RA . 2010. Mediator and cohesin connect gene expression and chromatin architecture. Nature 467 : 430 435.[PubMed] [CrossRef]
47. Tronche F,, Yaniv M . 1992. HNF1, a homeoprotein member of the hepatic transcription regulatory network. BioEssays 14 : 579 587.[PubMed] [CrossRef]
48. Chen X,, Xu H,, Yuan P,, Fang F,, Huss M,, Vega VB,, Wong E,, Orlov YL,, Zhang W,, Jiang J,, Loh YH,, Yeo HC,, Yeo ZX,, Narang V,, Govindarajan KR,, Leong B,, Shahab A,, Ruan Y,, Bourque G,, Sung WK,, Clarke ND,, Wei CL,, Ng HH . 2008. Integration of external signaling pathways with the core transcriptional network in embryonic stem cells. Cell 133 : 1106 1117.[PubMed] [CrossRef]
49. MacArthur S,, Li XY,, Li J,, Brown JB,, Chu HC,, Zeng L,, Grondona BP,, Hechmer A,, Simirenko L,, Keränen SV,, Knowles DW,, Stapleton M,, Bickel P,, Biggin MD,, Eisen MB . 2009. Developmental roles of 21 Drosophila transcription factors are determined by quantitative differences in binding to an overlapping set of thousands of genomic regions. Genome Biol 10 : R80. doi:10.1186/gb-2009-10-7-r80. [CrossRef]
50. Lupien M,, Eeckhoute J,, Meyer CA,, Wang Q,, Zhang Y,, Li W,, Carroll JS,, Liu XS,, Brown M . 2008. FoxA1 translates epigenetic signatures into enhancer-driven lineage-specific transcription. Cell 132 : 958 970.[PubMed] [CrossRef]
51. Odom DT,, Zizlsperger N,, Gordon DB,, Bell GW,, Rinaldi NJ,, Murray HL,, Volkert TL,, Schreiber J,, Rolfe PA,, Gifford DK,, Fraenkel E,, Bell GI,, Young RA . 2004. Control of pancreas and liver gene expression by HNF transcription factors. Science 303 : 1378 1381.[PubMed] [CrossRef]
52. Sandmann T,, Jensen LJ,, Jakobsen JS,, Karzynski MM,, Eichenlaub MP,, Bork P,, Furlong EE . 2006. A temporal map of transcription factor activity: Mef2 directly regulates target genes at all stages of muscle development. Dev Cell 10 : 797 807.[PubMed] [CrossRef]
53. Scott EW,, Simon MC,, Anastasi J,, Singh H . 1994. Requirement of transcription factor PU.1 in the development of multiple hematopoietic lineages. Science 265 : 1573 1577.[PubMed] [CrossRef]
54. McKercher SR,, Torbett BE,, Anderson KL,, Henkel GW,, Vestal DJ,, Baribault H,, Klemsz M,, Feeney AJ,, Wu GE,, Paige CJ,, Maki RA . 1996. Targeted disruption of the PU.1 gene results in multiple hematopoietic abnormalities. EMBO J 15 : 5647 5658.[PubMed]
55. Heinz S,, Benner C,, Spann N,, Bertolino E,, Lin YC,, Laslo P,, Cheng JX,, Murre C,, Singh H,, Glass CK . 2010. Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol Cell 38 : 576 589.[PubMed] [CrossRef]
56. Uhlenhaut NH,, Barish GD,, Yu RT,, Downes M,, Karunasiri M,, Liddle C,, Schwalie P,, Hübner N,, Evans RM . 2013. Insights into negative regulation by the glucocorticoid receptor from genome-wide profiling of inflammatory cistromes. Mol Cell 49 : 158 171.[PubMed] [CrossRef]
57. Heinz S,, Romanoski CE,, Benner C,, Allison KA,, Kaikkonen MU,, Orozco LD,, Glass CK . 2013. Effect of natural genetic variation on enhancer selection and function. Nature 503 : 487 492.[PubMed] [CrossRef]
58. Ostuni R,, Piccolo V,, Barozzi I,, Polletti S,, Termanini A,, Bonifacio S,, Curina A,, Prosperini E,, Ghisletti S,, Natoli G . 2013. Latent enhancers activated by stimulation in differentiated cells. Cell 152 : 157 171.[PubMed] [CrossRef]
59. Netea MG,, Joosten LA,, Latz E,, Mills KH,, Natoli G,, Stunnenberg HG,, O’Neill LA,, Xavier RJ . 2016. Trained immunity: a program of innate immune memory in health and disease. Science 352 : aaf1098. doi:10.1126/science.aaf1098. [PubMed] [CrossRef]
60. Gautier EL,, Shay T,, Miller J,, Greter M,, Jakubzick C,, Ivanov S,, Helft J,, Chow A,, Elpek KG,, Gordonov S,, Mazloom AR,, Ma’ayan A,, Chua WJ,, Hansen TH,, Turley SJ,, Merad M,, Randolph GJ , Immunological Genome Consortium . 2012. Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat Immunol 13 : 1118 1128.[PubMed] [CrossRef]
61. Ghosn EE,, Cassado AA,, Govoni GR,, Fukuhara T,, Yang Y,, Monack DM,, Bortoluci KR,, Almeida SR,, Herzenberg LA,, Herzenberg LA . 2010. Two physically, functionally, and developmentally distinct peritoneal macrophage subsets. Proc Natl Acad Sci U S A 107 : 2568 2573.[PubMed] [CrossRef]
62. Lavin Y,, Winter D,, Blecher-Gonen R,, David E,, Keren-Shaul H,, Merad M,, Jung S,, Amit I . 2014. Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell 159 : 1312 1326.[PubMed] [CrossRef]
63. Lara-Astiaso D,, Weiner A,, Lorenzo-Vivas E,, Zaretsky I,, Jaitin DA,, David E,, Keren-Shaul H,, Mildner A,, Winter D,, Jung S,, Friedman N,, Amit I . 2014. Immunogenetics. Chromatin state dynamics during blood formation. Science 345 : 943 949.[PubMed] [CrossRef]
64. Okabe Y,, Medzhitov R . 2014. Tissue-specific signals control reversible program of localization and functional polarization of macrophages. Cell 157 : 832 844.[PubMed] [CrossRef]
65. Brown JD,, Lin CY,, Duan Q,, Griffin G,, Federation AJ,, Paranal RM,, Bair S,, Newton G,, Lichtman AH,, Kung AL,, Yang T,, Wang H,, Luscinskas FW,, Croce KJ,, Bradner JE,, Plutzky J . 2014. NF-κB directs dynamic super enhancer formation in inflammation and atherogenesis. Mol Cell 56 : 219 231.[PubMed] [CrossRef]
66. Di Micco R,, Fontanals-Cirera B,, Low V,, Ntziachristos P,, Yuen SK,, Lovell CD,, Dolgalev I,, Yonekubo Y,, Zhang G,, Rusinova E,, Gerona-Navarro G,, Cañamero M,, Ohlmeyer M,, Aifantis I,, Zhou M-M,, Tsirigos A,, Hernando E . 2014. Control of embryonic stem cell identity by BRD4-dependent transcriptional elongation of super-enhancer-associated pluripotency genes. Cell Rep 9 : 234 247.[PubMed] [CrossRef]
67. Herranz D,, Ambesi-Impiombato A,, Palomero T,, Schnell SA,, Belver L,, Wendorff AA,, Xu L,, Castillo-Martin M,, Llobet-Navás D,, Cordon-Cardo C,, Clappier E,, Soulier J,, Ferrando AA . 2014. A NOTCH1-driven MYC enhancer promotes T cell development, transformation and acute lymphoblastic leukemia. Nat Med 20 : 1130 1137.[PubMed] [CrossRef]
68. Moreau-Gachelin F,, Wendling F,, Molina T,, Denis N,, Titeux M,, Grimber G,, Briand P,, Vainchenker W,, Tavitian A . 1996. Spi-1/PU.1 transgenic mice develop multistep erythroleukemias. Mol Cell Biol 16 : 2453 2463.[PubMed] [CrossRef]
69. Rosenbauer F,, Wagner K,, Kutok JL,, Iwasaki H,, Le Beau MM,, Okuno Y,, Akashi K,, Fiering S,, Tenen DG . 2004. Acute myeloid leukemia induced by graded reduction of a lineage-specific transcription factor, PU.1. Nat Genet 36 : 624 630.[PubMed] [CrossRef]
70. Schönheit J,, Kuhl C,, Gebhardt ML,, Klett FF,, Riemke P,, Scheller M,, Huang G,, Naumann R,, Leutz A,, Stocking C,, Priller J,, Andrade-Navarro MA,, Rosenbauer F . 2013. PU.1 level-directed chromatin structure remodeling at the Irf8 gene drives dendritic cell commitment. Cell Rep 3 : 1617 1628.[PubMed] [CrossRef]
71. Terry RL,, Miller SD . 2014. Molecular control of monocyte development. Cell Immunol 291 : 16 21.[PubMed] [CrossRef]
72. Carotta S,, Willis SN,, Hasbold J,, Inouye M,, Pang SHM,, Emslie D,, Light A,, Chopin M,, Shi W,, Wang H,, Morse HC III,, Tarlinton DM,, Corcoran LM,, Hodgkin PD,, Nutt SL . 2014. The transcription factors IRF8 and PU.1 negatively regulate plasma cell differentiation. J Exp Med 211 : 2169 2181.[PubMed] [CrossRef]
73. Kurotaki D,, Yamamoto M,, Nishiyama A,, Uno K,, Ban T,, Ichino M,, Sasaki H,, Matsunaga S,, Yoshinari M,, Ryo A,, Nakazawa M,, Ozato K,, Tamura T . 2014. IRF8 inhibits C/EBPα activity to restrain mononuclear phagocyte progenitors from differentiating into neutrophils. Nat Commun 5 : 4978. doi:10.1038/ncomms5978. [CrossRef]
74. Mancino A,, Termanini A,, Barozzi I,, Ghisletti S,, Ostuni R,, Prosperini E,, Ozato K,, Natoli G . 2015. A dual cis-regulatory code links IRF8 to constitutive and inducible gene expression in macrophages. Genes Dev 29 : 394 408.[PubMed] [CrossRef]
75. Kohyama M,, Ise W,, Edelson BT,, Wilker PR,, Hildner K,, Mejia C,, Frazier WA,, Murphy TL,, Murphy KM . 2009. Role for Spi-C in the development of red pulp macrophages and splenic iron homeostasis. Nature 457 : 318 321.[PubMed] [CrossRef]
76. Alfaqeeh S,, Oralova V,, Foxworthy M,, Matalova E,, Grigoriadis AE,, Tucker AS . 2015. Root and eruption defects in c-Fos mice are driven by loss of osteoclasts. J Dent Res 94 : 1724 1731.[PubMed] [CrossRef]
77. Grigoriadis AE,, Wang ZQ,, Cecchini MG,, Hofstetter W,, Felix R,, Fleisch HA,, Wagner EF . 1994. c-Fos: a key regulator of osteoclast-macrophage lineage determination and bone remodeling. Science 266 : 443 448.[PubMed] [CrossRef]
78. Johnson RS,, Spiegelman BM,, Papaioannou V . 1992. Pleiotropic effects of a null mutation in the c-fos proto-oncogene. Cell 71 : 577 586.[PubMed] [CrossRef]
79. Wang ZQ,, Ovitt C,, Grigoriadis AE,, Möhle-Steinlein U,, Rüther U,, Wagner EF . 1992. Bone and haematopoietic defects in mice lacking c-fos . Nature 360 : 741 745.[PubMed] [CrossRef]
80. Schneider C,, Nobs SP,, Kurrer M,, Rehrauer H,, Thiele C,, Kopf M . 2014. Induction of the nuclear receptor PPAR-γ by the cytokine GM-CSF is critical for the differentiation of fetal monocytes into alveolar macrophages. Nat Immunol 15 : 1026 1037.[PubMed] [CrossRef]
81. Hanna RN,, Shaked I,, Hubbeling HG,, Punt JA,, Wu R,, Herrley E,, Zaugg C,, Pei H,, Geissmann F,, Ley K,, Hedrick CC . 2012. NR4A1 (Nur77) deletion polarizes macrophages toward an inflammatory phenotype and increases atherosclerosis. Circ Res 110 : 416 427.[PubMed] [CrossRef]
82. Butovsky O,, Jedrychowski MP,, Moore CS,, Cialic R,, Lanser AJ,, Gabriely G,, Koeglsperger T,, Dake B,, Wu PM,, Doykan CE,, Fanek Z,, Liu L,, Chen Z,, Rothstein JD,, Ransohoff RM,, Gygi SP,, Antel JP,, Weiner HL . 2014. Identification of a unique TGF-β-dependent molecular and functional signature in microglia. Nat Neurosci 17 : 131 143.[PubMed] [CrossRef]
83. Adam RC,, Yang H,, Rockowitz S,, Larsen SB,, Nikolova M,, Oristian DS,, Polak L,, Kadaja M,, Asare A,, Zheng D,, Fuchs E . 2015. Pioneer factors govern super-enhancer dynamics in stem cell plasticity and lineage choice. Nature 521 : 366 370.[PubMed] [CrossRef]
84. Zhang X,, Choi PS,, Francis JM,, Imielinski M,, Watanabe H,, Cherniack AD,, Meyerson M . 2016. Identification of focally amplified lineage-specific super-enhancers in human epithelial cancers. Nat Genet 48 : 176 182.[PubMed] [CrossRef]
85. Sweeney CL,, Teng R,, Wang H,, Merling RK,, Lee J,, Choi U,, Koontz S,, Wright DG,, Malech HL . 2016. Molecular analysis of neutrophil differentiation from human iPSCs delineates the kinetics of key regulators of hematopoiesis. Stem Cells 34 : 1513 1526.[PubMed] [CrossRef]
86. Thomas S,, Bonchev D . 2010. A survey of current software for network analysis in molecular biology. Hum Genomics 4 : 353 360.[PubMed] [CrossRef]
87. Buenrostro JD,, Giresi PG,, Zaba LC,, Chang HY,, Greenleaf WJ . 2013. Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position. Nat Methods 10 : 1213 1218.[PubMed] [CrossRef]
88. Bao X,, Rubin AJ,, Qu K,, Zhang J,, Giresi PG,, Chang HY,, Khavari PA . 2015. A novel ATAC-seq approach reveals lineage-specific reinforcement of the open chromatin landscape via cooperation between BAF and p63. Genome Biol 16 : 284. doi:10.1186/s13059-015-0840-9. [CrossRef]
89. Ackermann AM,, Wang Z,, Schug J,, Naji A,, Kaestner KH . 2016. Integration of ATAC-seq and RNA-seq identifies human alpha cell and beta cell signature genes. Mol Metab 5 : 233 244.[PubMed] [CrossRef]
90. Davie K,, Jacobs J,, Atkins M,, Potier D,, Christiaens V,, Halder G,, Aerts S . 2015. Discovery of transcription factors and regulatory regions driving in vivo tumor development by ATAC-seq and FAIRE-seq open chromatin profiling. PLoS Genet 11 : e1004994. doi:10.1371/journal.pgen.1004994. [CrossRef]
91. Jinek M,, Chylinski K,, Fonfara I,, Hauer M,, Doudna JA,, Charpentier E . 2012. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science 337 : 816 821.[PubMed] [CrossRef]
92. Jinek M,, East A,, Cheng A,, Lin S,, Ma E,, Doudna J . 2013. RNA-programmed genome editing in human cells. eLife 2 : e00471. doi:10.7554/eLife.00471. [PubMed] [CrossRef]
93. Cong L,, Ran FA,, Cox D,, Lin S,, Barretto R,, Habib N,, Hsu PD,, Wu X,, Jiang W,, Marraffini LA,, Zhang F . 2013. Multiplex genome engineering using CRISPR/Cas systems. Science 339 : 819 823.[PubMed] [CrossRef]
94. Perez-Pinera P,, Kocak DD,, Vockley CM,, Adler AF,, Kabadi AM,, Polstein LR,, Thakore PI,, Glass KA,, Ousterout DG,, Leong KW,, Guilak F,, Crawford GE,, Reddy TE,, Gersbach CA . 2013. RNA-guided gene activation by CRISPR-Cas9-based transcription factors. Nat Methods 10 : 973 976.[PubMed] [CrossRef]
95. Gilbert LA,, Larson MH,, Morsut L,, Liu Z,, Brar GA,, Torres SE,, Stern-Ginossar N,, Brandman O,, Whitehead EH,, Doudna JA,, Lim WA,, Weissman JS,, Qi LS . 2013. CRISPR-mediated modular RNA-guided regulation of transcription in eukaryotes. Cell 154 : 442 451.[PubMed] [CrossRef]
96. Lewis WR,, Malarkey EB,, Tritschler D,, Bower R,, Pasek RC,, Porath JD,, Birket SE,, Saunier S,, Antignac C,, Knowles MR,, Leigh MW,, Zariwala MA,, Challa AK,, Kesterson RA,, Rowe SM,, Drummond IA,, Parant JM,, Hildebrandt F,, Porter ME,, Yoder BK,, Berbari NF . 2016. Mutation of growth arrest specific 8 reveals a role in motile cilia function and human disease. PLoS Genet 12 : e1006220. doi:10.1371/journal.pgen.1006220.
97. Lee JS,, Grav LM,, Pedersen LE,, Lee GM,, Kildegaard HF . 2016. Accelerated homology-directed targeted integration of transgenes in Chinese hamster ovary cells via CRISPR/Cas9 and fluorescent enrichment. Biotechnol Bioeng doi:10.1002/bit.26002. [CrossRef]
98. Fujita T,, Fujii H . 2013. Efficient isolation of specific genomic regions and identification of associated proteins by engineered DNA-binding molecule-mediated chromatin immunoprecipitation (enChIP) using CRISPR. Biochem Biophys Res Commun 439 : 132 136.[PubMed] [CrossRef]
99. Nicodeme E,, Jeffrey KL,, Schaefer U,, Beinke S,, Dewell S,, Chung CW,, Chandwani R,, Marazzi I,, Wilson P,, Coste H,, White J,, Kirilovsky J,, Rice CM,, Lora JM,, Prinjha RK,, Lee K,, Tarakhovsky A . 2010. Suppression of inflammation by a synthetic histone mimic. Nature 468 : 1119 1123.[PubMed] [CrossRef]
100. Lovén J,, Hoke HA,, Lin CY,, Lau A,, Orlando DA,, Vakoc CR,, Bradner JE,, Lee TI,, Young RA . 2013. Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell 153 : 320 334.[PubMed] [CrossRef]

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error