Transcriptional regulation of granulopoiesis

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Homo sapiens
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Neutrophilic granulocytes (hereafter called granulocytes) are distinguished by multilobulated nuclei and presence of cytoplasmic granules containing antipathogenic proteins (reviewed in Cowland and Borregaard 2016, Yin and Heit 2018). Granulocytes comprise eosinophils, basophils, mast cells, and neutrophils, all of which are ultimately derived from hemopoietic stem cells (HSCs), a self-renewing population of stem cells located in the bone marrow. A portion of HSCs exit self-renewing proliferation and differentiate to form multipotent progenitors (MPPs). MPPs then differentiate to form common myeloid progenitors (CMPs) as well as the erythrocyte lineage. CMPs further differentiate into granulocyte-monocyte progenitors (GMPs) which can then differentiate into monocytes or any of the types of granulocytes (reviewed in Fiedler and Brunner 2012). granulocytes are the most abundant leukocytes in peripheral blood.
For early granulopoiesis the CEBPA, SPI1 (PU.1), RAR, CBF, and MYB transcription factors are essential. CEBPE, SPI1, SP1, CDP, and HOXA10 transcription factors initiate terminal neutrophil differentiation.
Initially, RUNX1 activates SPI1 (PU.1), which is believed to be the key transcription factor driving the formation of MPPs and CMPs (reviewed in Friedman 2007, Fiedler and Brunner 2012). SPI1, in turn, activates expression of CEBPA, an indispensable transcription factor for granulopoiesis especially important in the transition from CMP to GMP (inferred from mouse homologs in Wilson et al. 2010, Guo et al. 2012, Guo et al. 2014, Cooper et al. 2015). CEBPA, in turn, activates the expression of several transcription factors and receptors characteristic of granulocytes, including CEBPA (autoregulation), CEBPE (Loke et al. 2018, and inferred from mouse homologs in Wang and Friedman 2002, Friedman et al. 2003), GFI1 (inferred from mouse homologs in Lidonnici et al. 2010), KLF5 (Federzoni et al. 2014), IL6R (inferred from mouse homologs in Zhang et al. 1998), and CSF3R (Smith et al. 1996). Importantly, CEBPA dimers repress transcription of MYC (c-Myc) (Johansen et al. 2001, and inferred from mouse homologs in Slomiany et al. 2000, Porse et al. 2001). CEBPA binds CDK2 and CDK4 (Wang et al. 2001) which inhibits their kinase activity by disrupting their association with cyclins thereby limiting proliferation and favoring differentiation of granulocyte progenitors during regular ("steady-state") granulopoiesis (reviewed in Friedman 2015). The transcription factor GFI1 regulates G-CSF signaling and neutrophil development through the Ras activator RasGRP1 (de la Luz Sierra et al. 2010).
Inhibitors of DNA binding (ID) proteins ID1 and ID2 regulate granulopoiesis and eosinophil production such that ID1 induces neutrophil development and inhibits eosinophil differentiation, whereas ID2 induces both eosinophil and neutrophil development (Buitenhuis et al. 2005, Skokowa et al. 2009).
Major infection activates emergency granulopoiesis (reviewed in Manz and Boettcher 2014, Hirai et al. 2015), the production of large numbers of granulocytes in a relatively short period of time. Emergency granulopoiesis is activated by cytokines, CSF2 (GM-CSF) and especially CSF3 (G-CSF, reviewed in Panopoulos and Watowich 2008, Liongue et al. 2009) which bind receptors, CSF2R and CSF3R, respectively, resulting in expression of CEBPB, which interferes with repression of MYC by CEBPA (inferred from mouse homologs in Zhang et al. 2010) and represses MYC less than CEBPA does (Hirai et al. 2006), leading to proliferation of granulocyte progenitors prior to final differentiation.Both, emergency and steady-state granulopoiesis are regulated by direct interaction of CEBPA (steady-state) or CEBPB (emergency) proteins with NAD+-dependent protein deacetylases, SIRT1 and SIRT2 (Skokowa et al. 2009). G-CSF induces the NAD+-generating enzyme, Nicotinamide phosphoribosyltransferase (NAMPT, or PBEF), that in turn activates sirtuins (Skokowa et al. 2009).
GADD45A and GADD45B proteins are essential for stress-induced granulopoiesis and granulocyte chemotaxis by activation of p38 kinase (Gupta et al. 2006, Salerno et al. 2012). SHP2 is required for induction of CEBPA expression and granulopoiesis in response to CSF3 (G-CSF) or other cytokines independent of SHP2-mediated ERK activation (Zhang et al. 2011).
Transcription of neutrophil granule proteins (e.g. ELANE, MPO, AZU1, DEFA4), that play an essential role in bacterial killing are regulated by CEBPE and SPI1 (PU.1) transcription factors (Gombart et al. 2003, Nakajima et al. 2006). RUNX1 and LEF1 also regulate ELANE (ELA2) mRNA expression by binding to its promoter (Li et al. 2003).

Literature References
PubMed ID Title Journal Year
10913181 C/EBPalpha inhibits cell growth via direct repression of E2F-DP-mediated transcription

Slomiany, BA, D'Arigo, KL, Kurtz, DT, Kelly, MM

Mol. Cell. Biol. 2000
9743535 Upregulation of interleukin 6 and granulocyte colony-stimulating factor receptors by transcription factor CCAAT enhancer binding protein alpha (C/EBP alpha) is critical for granulopoiesis

Datta, MW, Zhang, P, Tenen, DG, Darlington, GJ, Iwama, A, Link, DC

J. Exp. Med. 1998
24751955 Emergency granulopoiesis

Boettcher, S, Manz, MG

Nat. Rev. Immunol. 2014
16531405 N-terminal region of CCAAT/enhancer-binding protein epsilon is critical for cell cycle arrest, apoptosis, and functional maturation during myeloid differentiation

Watanabe, N, Shibata, F, Nakajima, H, Ikeda, Y, Handa, M, Kitamura, T

J. Biol. Chem. 2006
29185068 Armed for destruction: formation, function and trafficking of neutrophil granules

Yin, C, Heit, B

Cell Tissue Res. 2018
8695841 PU.1 (Spi-1) and C/EBP alpha regulate the granulocyte colony-stimulating factor receptor promoter in myeloid cells

Dziennis, SE, Gonzalez, DA, Smith, LT, Tenen, DG, Hohaus, S

Blood 1996
27558325 Granulopoiesis and granules of human neutrophils

Cowland, JB, Borregaard, N

Immunol. Rev. 2016
22432088 The role of transcription factors in the guidance of granulopoiesis

Fiedler, K, Brunner, C

Am J Blood Res 2012
19699815 Granulocyte colony-stimulating factor receptor: stimulating granulopoiesis and much more

Liongue, C, Ward, AC, Russell, AP, Wright, C

Int. J. Biochem. Cell Biol. 2009
20924107 Expression of the transcriptional repressor Gfi-1 is regulated by C/EBP{alpha} and is involved in its proliferation and colony formation-inhibitory effects in p210BCR/ABL-expressing cells

Calabretta, B, Soliera, AR, Ferrari-Amorotti, G, Martinez, RV, Zhang, Y, Prisco, M, Lidonnici, MR, Audia, A, Holyoake, TL, Waldron, T, Donato, N

Cancer Res. 2010
20203268 The transcription factor Gfi1 regulates G-CSF signaling and neutrophil development through the Ras activator RasGRP1

Qian, X, de la Luz Sierra, M, Zhu, J, Sakakibara, S, Salvucci, O, Gasperini, P, Segarra, M, Jiang, K, McCormick, PJ, Stone, J, Tosato, G, Maric, D, Lowy, DR

Blood 2010
15701714 Differential regulation of granulopoiesis by the basic helix-loop-helix transcriptional inhibitors Id1 and Id2

Lammers, JW, Jacobsen, SE, Buitenhuis, M, Castor, A, Koenderman, L, Verhagen, LP, van Deutekom, HW, Coffer, PJ

Blood 2005
24584857 CEBPA-dependent HK3 and KLF5 expression in primary AML and during AML differentiation

Tschan, MP, Humbert, M, Fey, MF, Federzoni, EA, Behre, G, Torbett, BE

Sci Rep 2014
25940801 Non-steady-state hematopoiesis regulated by the C/EBPβ transcription factor

Hirai, H, Yokota, A, Maekawa, T, Sato, A, Tamura, A

Cancer Sci. 2015
21725048 SHP2 tyrosine phosphatase stimulates CEBPA gene expression to mediate cytokine-dependent granulopoiesis

Zhang, L, Friedman, AD

Blood 2011
22307729 Gadd45a and Gadd45b modulate innate immune functions of granulocytes and macrophages by differential regulation of p38 and JNK signaling

Salerno, DM, Hoffman, B, Liebermann, DA, Tront, JS

J. Cell. Physiol. 2012
18400509 Granulocyte colony-stimulating factor: molecular mechanisms of action during steady state and 'emergency' hematopoiesis

Panopoulos, AD, Watowich, SS

Cytokine 2008
29593731 Transcriptional Regulation of Emergency Granulopoiesis in Leukemia

Rizvi, A, Hasan, S, Naqvi, AR

Front Immunol 2018
17934488 Transcriptional control of granulocyte and monocyte development

Friedman, AD

Oncogene 2007
24868087 The Cebpa +37-kb enhancer directs transgene expression to myeloid progenitors and to long-term hematopoietic stem cells

Guo, H, Friedman, AD, Ma, O

J. Leukoc. Biol. 2014
16732331 Hematopoietic cells from gadd45a-deficient and gadd45b-deficient mice exhibit impaired stress responses to acute stimulation with cytokines, myeloablation and inflammation

Hoffman, B, Gupta, M, Liebermann, DA, Gupta, SK

Oncogene 2006
11340171 c-Myc is a critical target for c/EBPalpha in granulopoiesis

Felsher, DW, Tenen, DG, Lodie, TA, Johansen, LM, Sasaki, K, Iwama, A, Golub, TR

Mol. Cell. Biol. 2001
19796237 Dysregulation of myeloid-specific transcription factors in congenital neutropenia

Welte, K, Skokowa, J

Ann. N. Y. Acad. Sci. 2009
11684017 C/EBPalpha arrests cell proliferation through direct inhibition of Cdk2 and Cdk4

Welm, A, Iakova, P, Roesler, WJ, Goode, T, Wilde, M, Timchenko, NA, Wang, H

Mol. Cell 2001
25938608 The +37 kb Cebpa Enhancer Is Critical for Cebpa Myeloid Gene Expression and Contains Functional Sites that Bind SCL, GATA2, C/EBPα, PU.1, and Additional Ets Factors

Guo, H, Cooper, S, Friedman, AD

PLoS ONE 2015
19182797 NAMPT is essential for the G-CSF-induced myeloid differentiation via a NAD(+)-sirtuin-1-dependent pathway

Thakur, BK, Welte, K, Gupta, K, Gaestel, M, Cario, G, Skokowa, J, Meyer, G, Lan, D, Brechlin, AM, Schambach, A, Tong, Q, Hinrichsen, L, Stanulla, M, Wang, F

Nat. Med. 2009
16751774 C/EBPbeta is required for 'emergency' granulopoiesis

Hirai, H, Dayaram, T, Hetherington, CJ, Imanishi, J, Zhang, P, Tenen, DG, Mizuno, S, Akashi, K

Nat. Immunol. 2006
20887958 Combinatorial transcriptional control in blood stem/progenitor cells: genome-wide analysis of ten major transcriptional regulators

Schütte, J, Pimanda, JE, Göttgens, B, Foster, SD, Dzierzak, E, Chilarska, PM, de Bruijn, MF, Ouwehand, WH, Wang, X, Kaimakis, P, Knezevic, K, Kinston, S, Wilson, NK

Cell Stem Cell 2010
29431622 C/EBPα overrides epigenetic reprogramming by oncogenic transcription factors in acute myeloid leukemia

Pickin, A, Imperato, MR, Bonifer, C, Ptasinska, A, Cockerill, PN, Loke, J, Keane, P, Assi, SA, Chin, PS

Blood Adv 2018
20581311 STAT3 controls myeloid progenitor growth during emergency granulopoiesis

Murray, PJ, Nguyen-Jackson, H, Panopoulos, AD, Li, HS, Zhang, H, Watowich, SS

Blood 2010
11672531 E2F repression by C/EBPalpha is required for adipogenesis and granulopoiesis in vivo

Pedersen, TA, Friis-Hansen, L, Xu, X, Nerlov, C, Wewer, UM, Porse, BT, Lindberg, B

Cell 2001
22451420 Runx1 deletion or dominant inhibition reduces Cebpa transcription via conserved promoter and distal enhancer sites to favor monopoiesis over granulopoiesis

Guo, H, Speck, NA, Friedman, AD, Ma, O

Blood 2012
11929766 CCAAT/enhancer-binding proteins are required for granulopoiesis independent of their induction of the granulocyte colony-stimulating factor receptor

Friedman, AD, Wang, QF

Blood 2002
14636649 Regulation of granulocyte and monocyte differentiation by CCAAT/enhancer binding protein alpha

Friedman, AD, Kummalue, T, Cleaves, R, Liu, H, Keefer, JR, Wang, QF

Blood Cells Mol. Dis. 2003
12515729 Regulation of neutrophil and eosinophil secondary granule gene expression by transcription factors C/EBP epsilon and PU.1

Yamaguchi, Y, Gombart, AF, Koeffler, HP, Kwok, SH, Torbett, BE, Anderson, KL

Blood 2003
25753223 C/EBPα in normal and malignant myelopoiesis

Friedman, AD

Int. J. Hematol. 2015
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