Transcriptional regulation by RUNX1

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R-HSA-8878171
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Homo sapiens
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The RUNX1 (AML1) transcription factor is a master regulator of hematopoiesis (Ichikawa et al. 2004) that is frequently translocated in acute myeloid leukemia (AML), resulting in formation of fusion proteins with altered transactivation profiles (Lam and Zhang 2012, Ichikawa et al. 2013). In addition to RUNX1, its heterodimerization partner CBFB is also frequently mutated in AML (Shigesada et al. 2004, Mangan and Speck 2011).
The core domain of CBFB binds to the Runt domain of RUNX1, resulting in formation of the RUNX1:CBFB heterodimer. CBFB does not interact with DNA directly. The Runt domain of RUNX1 mediated both DNA binding and heterodimerization with CBFB (Tahirov et al. 2001), while RUNX1 regions that flank the Runt domain are involved in transactivation (reviewed in Zhang et al. 2003) and negative regulation (autoinhibition). CBFB facilitates RUNX1 binding to DNA by stabilizing Runt domain regions that interact with the major and minor grooves of the DNA (Tahirov et al. 2001, Backstrom et al. 2002, Bartfeld et al. 2002). The transactivation domain of RUNX1 is located C-terminally to the Runt domain and is followed by the negative regulatory domain. Autoinhibiton of RUNX1 is relieved by interaction with CBFB (Kanno et al. 1998).
Transcriptional targets of the RUNX1:CBFB complex involve genes that regulate self-renewal of hematopoietic stem cells (HSCs) (Zhao et al. 2014), as well as commitment and differentiation of many hematopoietic progenitors, including myeloid (Friedman 2009) and megakaryocytic progenitors (Goldfarb 2009), regulatory T lymphocytes (Wong et al. 2011) and B lymphocytes (Boller and Grosschedl 2014).
RUNX1 binds to promoters of many genes involved in ribosomal biogenesis (Ribi) and is thought to stimulate their transcription. RUNX1 loss-of-function decreases ribosome biogenesis and translation in hematopoietic stem and progenitor cells (HSPCs). RUNX1 loss-of-function is therefore associated with a slow growth, but at the same time it results in reduced apoptosis and increases resistance of cells to genotoxic and endoplasmic reticulum stress, conferring an overall selective advantage to RUNX1 deficient HSPCs (Cai et al. 2015).
RUNX1 is implicated as a tumor suppressor in breast cancer. RUNX1 forms a complex with the activated estrogen receptor alpha (ESR1) and regulates expression of estrogen-responsive genes (Chimge and Frenkel 2013).
RUNX1 is overexpressed in epithelial ovarian carcinoma where it may contribute to cell proliferation, migration and invasion (Keita et al. 2013).
RUNX1 may cooperate with TP53 in transcriptional activation of TP53 target genes upon DNA damage (Wu et al. 2013).
RUNX1 is needed for the maintenance of skeletal musculature (Wang et al. 2005).
During mouse embryonic development, Runx1 is expressed in most nociceptive sensory neurons, which are involved in the perception of pain. In adult mice, Runx1 is expressed only in nociceptive sensory neurons that express the Ret receptor and is involved in regulation of expression of genes encoding ion channels (sodium-gated, ATP-gated and hydrogen ion-gated) and receptors (thermal receptors, opioid receptor MOR and the Mrgpr class of G protein coupled receptors). Mice lacking Runx1 show defective perception of thermal and neuropathic pain (Chen CL et al. 2006). Runx1 is thought to activate the neuronal differentiation of nociceptive dorsal root ganglion cells during embryonal development possibly through repression of Hes1 expression (Kobayashi et al. 2012). In chick and mouse embryos, Runx1 expression is restricted to the dorso-medial domain of the dorsal root ganglion, to TrkA-positive cutaneous sensory neurons. Runx3 expression in chick and mouse embryos is restricted to ventro-lateral domain of the dorsal root ganglion, to TrkC-positive proprioceptive neurons (Chen AI et al. 2006, Kramer et al. 2006). RUNX1 mediated regulation of neuronally expressed genes will be annotated when mechanistic details become available.

Literature References
PubMed ID Title Journal Year
16446143 Graded activity of transcription factor Runx3 specifies the laminar termination pattern of sensory axons in the developing spinal cord

Chen, AI, de Nooij, JC, Jessell, TM

Neuron 2006
15156186 Mechanism of leukemogenesis by the inv(16) chimeric gene CBFB/PEBP2B-MHY11

Shigesada, K, van De Sluis, B, Liu, PP

Oncogene 2004
23442798 The RUNX1 transcription factor is expressed in serous epithelial ovarian carcinoma and contributes to cell proliferation, migration and invasion

Keita, M, Bachvarova, M, Morin, C, Plante, M, Gregoire, J, Renaud, MC, Sebastianelli, A, Trinh, XB, Bachvarov, D

Cell Cycle 2013
12732176 Structural and functional characterization of Runx1, CBF beta, and CBF beta-SMMHC

Zhang, L, Lukasik, SM, Speck, NA, Bushweller, JH

Blood Cells Mol. Dis. 2003
23613270 A role for RUNX1 in hematopoiesis and myeloid leukemia

Ichikawa, M, Yoshimi, A, Nakagawa, M, Nishimoto, N, Watanabe-Okochi, N, Kurokawa, M

Int. J. Hematol. 2013
16446141 Runx1 determines nociceptive sensory neuron phenotype and is required for thermal and neuropathic pain

Chen, CL, Broom, DC, Liu, Y, de Nooij, JC, Li, Z, Cen, C, Samad, OA, Jessell, TM, Woolf, CJ, Ma, Q

Neuron 2006
21906677 Runx1 promotes neuronal differentiation in dorsal root ganglion

Kobayashi, A, Senzaki, K, Ozaki, S, Yoshikawa, M, Shiga, T

Mol. Cell. Neurosci. 2012
15213471 Runx1/AML-1 ranks as a master regulator of adult hematopoiesis

Ichikawa, M, Asai, T, Chiba, S, Kurokawa, M, Ogawa, S

Cell Cycle 2004
9566865 Intrinsic transcriptional activation-inhibition domains of the polyomavirus enhancer binding protein 2/core binding factor alpha subunit revealed in the presence of the beta subunit

Kanno, T, Kanno, Y, Chen, LF, Ogawa, E, Kim, WY, Ito, Y

Mol. Cell. Biol. 1998
25123279 The regulatory network of B-cell differentiation: a focused view of early B-cell factor 1 function

Boller, S, Grosschedl, R

Immunol. Rev. 2014
12217689 The RUNX1 Runt domain at 1.25A resolution: a structural switch and specifically bound chloride ions modulate DNA binding

Bäckström, S, Wolf-Watz, M, Grundström, C, Härd, T, Grundström, T, Sauer, UH

J. Mol. Biol. 2002
22150309 RUNX1 mutations in clonal myeloid disorders: from conventional cytogenetics to next generation sequencing, a story 40 years in the making

Mangan, JK, Speck, NA

Crit Rev Oncog 2011
21091910 Interplay of transcription factors in T-cell differentiation and function: the role of Runx

Wong, WF, Kohu, K, Chiba, T, Sato, T, Satake, M

Immunology 2011
16024660 Runx1 prevents wasting, myofibrillar disorganization, and autophagy of skeletal muscle

Wang, X, Blagden, C, Fan, J, Nowak, SJ, Taniuchi, I, Littman, DR, Burden, SJ

Genes Dev. 2005
19350569 Megakaryocytic programming by a transcriptional regulatory loop: A circle connecting RUNX1, GATA-1, and P-TEFb

Goldfarb, AN

J. Cell. Biochem. 2009
16446142 A role for Runx transcription factor signaling in dorsal root ganglion sensory neuron diversification

Kramer, I, Sigrist, M, de Nooij, JC, Taniuchi, I, Jessell, TM, Arber, S

Neuron 2006
26165925 Runx1 Deficiency Decreases Ribosome Biogenesis and Confers Stress Resistance to Hematopoietic Stem and Progenitor Cells

Cai, X, Gao, L, Teng, L, Ge, J, Oo, ZM, Kumar, AR, Gilliland, DG, Mason, PJ, Tan, K, Speck, NA

Cell Stem Cell 2015
19235904 Cell cycle and developmental control of hematopoiesis by Runx1

Friedman, AD

J. Cell. Physiol. 2009
22201794 RUNX1 and RUNX1-ETO: roles in hematopoiesis and leukemogenesis

Lam, K, Zhang, DE

Front Biosci (Landmark Ed) 2012
23148227 Runt-related transcription factor 1 (RUNX1) stimulates tumor suppressor p53 protein in response to DNA damage through complex formation and acetylation

Wu, D, Ozaki, T, Yoshihara, Y, Kubo, N, Nakagawara, A

J. Biol. Chem. 2013
24449215 Downregulation of RUNX1/CBFβ by MLL fusion proteins enhances hematopoietic stem cell self-renewal

Zhao, X, Chen, A, Yan, X, Zhang, Y, He, F, Hayashi, Y, Dong, Y, Rao, Y, Li, B, Conway, RM, Maiques-Diaz, A, Elf, SE, Huang, N, Zuber, J, Xiao, Z, Tse, W, Tenen, DG, Wang, Q, Chen, W, Mulloy, JC, Nimer, SD, Huang, G

Blood 2014
11257229 Structural analyses of DNA recognition by the AML1/Runx-1 Runt domain and its allosteric control by CBFbeta

Tahirov, TH, Inoue-Bungo, T, Morii, H, Fujikawa, A, Sasaki, M, Kimura, K, Shiina, M, Sato, K, Kumasaka, T, Yamamoto, M, Ishii, S, Ogata, K

Cell 2001
23045283 The RUNX family in breast cancer: relationships with estrogen signaling

Chimge, NO, Frenkel, B

Oncogene 2013
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