Transcriptional regulation by RUNX1

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, 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. 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.

Transcriptional targets of the RUNX1:CBFB complex involve genes that regulate self-renewal of hematopoietic stem cells (HSCs), as well as commitment and differentiation of many hematopoietic progenitors, including myeloid and megakaryocytic progenitors, regulatory T lymphocytes and B lymphocytes.

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.

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.

RUNX1 is overexpressed in epithelial ovarian carcinoma where it may contribute to cell proliferation, migration and invasion.

RUNX1 may cooperate with TP53 in transcriptional activation of TP53 target genes upon DNA damage.

RUNX1 is needed for the maintenance of skeletal musculature.

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. 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.