| ESRRB is an orphan nuclear receptor of the estrogen‑related receptor family that binds DNA as a monomer or homodimer on ERRE/ERE‑like motifs and functions as a sequence‑specific transcription factor integrating pluripotency, trophoblast and placental development, metabolic control, and lineage‑specific differentiation, with particularly prominent roles in early mouse development and stem‑cell self‑renewal. The protein contains the canonical nuclear receptor modular organization with an N‑terminal activation domain, a central zinc‑finger DNA‑binding domain that recognizes the consensus ERRE sequence 5′‑TCAAGGTCA‑3′ and related half‑sites, and a C‑terminal ligand‑binding/AF‑2 domain that recruits coactivators and corepressors; ESRRB binds these motifs on promoters and enhancers of key regulators including POU5F1/Oct4, NR0B1/Dax1, GATA6, ELF5, and EOMES, and remains associated with a subset of these loci through mitosis as a bookmarking factor to ensure rapid transcriptional reactivation in early G1. In naïve embryonic stem cells and trophoblast stem cells, ESRRB acts downstream of NANOG and cooperates with SOX2, Oct4, KDM1A, and NCOA3 to enforce self‑renewal and pluripotency in a largely LIF‑independent manner, activating transcription of pluripotency and trophoblast self‑renewal genes while repressing programs that drive epiblast stem cell transition and oxidative‑stress responses, such as NFE2L2‑dependent transcription and ESR1 activity. ESRRB directly binds and activates enhancers of ELF5, EOMES, and CDX2 in trophoblast lineages upon FGF signaling, promotes proliferation of diploid trophoblasts, and is essential for normal chorion formation and early placentation, as demonstrated by Esrrb‑null mouse models where mutations cause abnormal chorionic development, defective trophoblast proliferation, and mid‑gestation lethality. In the embryo proper, ESRRB expression in pluripotent and multipotent populations supports naive‑to‑formative transitions of the epiblast and contributes to primordial germ cell specification; depletion of Esrrb from ES cells leads to loss of ES morphology, downregulation of pluripotency markers, and derepression of differentiation genes, while forced ESRRB expression can replace NANOG in reprogramming and rescue self‑renewal of Nanog‑deficient cells, highlighting its central position in the core pluripotency circuitry. Beyond early development, ESRRB regulates rod photoreceptor‑specific genes and is required for the survival of rod cells, and in the inner ear it controls expression of ion channels and transporters necessary for endolymph homeostasis, with human ESRRB mutations linked to autosomal‑recessive nonsyndromic hearing impairment. |
