AT-rich interactive domain (ARID) proteins, first recognized in 1997, are a family of 15 proteins which binds to AT-rich regions of DNA ^[1][2]. ARID proteins play an important role in cell proliferation, differentiation, and development, and are upregulated in tumorous tissues ^[3]. The subfamilies of ARID proteins include ARID1, ARID2, ARID3, ARID4, ARID5, JARID1, and JARID2. The ARID3 subfamily has three members including ARID3A, ARID3B, and ARID3C. Although most of the ARID proteins act as tumor suppressors, ARID3A and ARID3B promote tumorigenesis ^[1]. ARID3A inhibits cell differentiation, promotes cell proliferation, and increases survival potential of cells ^[3][4], whereas ARID3B promotes proliferation, invasion, and migration of cancer cells ^[5][6][7]. However, ARID3B is more widely expressed in different tissues compared to ARID3A, suggesting more involvement of ARID3B in biological functions ^[2]. ARID3A and ARID3B are structurally similar and bind a similar region of DNA. Both ARID3A and ARID3B have an extended central ARID domain and two conserved amino acid domains at the C-terminal, termed REKLES α and REKLES β. Only members of the ARID3 subfamily have REKLES domains ^[8].

In contrast to ARID3B which is exclusively localized in the nucleus, ARID3A shuttles between the nucleus and cytoplasm. Once in the nucleus, ARID3A interacts with ARID3B through REKLES β domain. Therefore localization of ARID3A in the nucleus is dependent on its interaction with ARID3B in the nucleus, suggesting the dominant role of ARID3B ^[8][9]. In cancer cells, ARID3A and ARID3B recruit histone demethylase 4C (KDM4C) to make a tri-protein complex, called the ARID3B complex ^[10]. The ARID3B complex binds in the promoter areas of stemness genes and let-7 target genes, leading to histone demethylation by KDM4C and increased gene expression by initiation of transcription ^[10]. Therefore, genes regulated by the ARID3B complex also include let-7 miRNA target genes. Liao et al. further demonstrated that both ARID3A and ARID3B are targeted by let-7 miRNAs. Hence, other than directly targeting the mRNAs of target genes, let-7 miRNA can indirectly regulate their target genes by targeting and reducing the expression of ARID3A and ARID3B (Figure 1) ^[10][11].

For a long time, transcription activating proteins were thought to be the main regulators of gene expression in cells. However, in recent years microRNAs have emerged as “regulators of the regulators”. miRNAs regulate important processes in trophoblast cells including cell proliferation, differentiation, invasion, and migration. Although identification of widespread let-7 miRNA target genes makes them an important player in placental development, the role of other miRNAs and molecular pathways in placental development cannot be ignored. Although different studies have reported reduced LIN28 and high let-7 miRNAs in term human placentas from preeclamptic and IUGR pregnancies, the exact cause of this dysregulation is not clear. Epigenetic modifications due to adverse uterine environment, random genetic mutations, prenatal insults like hypoxia, oxidative stress, maternal malnutrition, and gestational stress are some of the possible factors which can dysregulate LIN28-let-7 axis in trophoblast cells. LIN28-let-7-ARID3B pathway regulates trophoblast cell proliferation by modulating the expression of proliferation associated genes in vitro and in vivo. The trophoblast cells with low LIN28 will have high let-7 miRNAs and low ARID3B. There are two possible pathways of regulation of proliferation-associated genes by let-7 miRNAs in trophoblast cells (Figure 2). One pathway involves binding of let-7 miRNAs in 3ʹ-UTR of their target mRNA leading to mRNA degradation or translational repression. Secondly, let-7 miRNAs target ARID3A, ARID3B, and KDM4C to inhibit or reduce transcriptional activation of proliferation-associated genes by the ARID3B complex. Therefore, trophoblast cells with high let-7 miRNAs will have reduced expression of proliferation factors and more of a tendency to differentiate. High let-7 miRNAs during early placental development reduce cell proliferation, invasion, and migration of trophoblast cells, leading to placental abnormalities. Let-7 miRNAs might be the major players in pathogenesis of placenta-associated disorders. miRNAs can be readily measured in peripheral blood, tissue biopsies, saliva, cerebrospinal fluid, urine, and other biological samples. High let-7 miRNAs are upregulated in IUGR and preeclamptic placentas, suggesting that let-7 miRNAs can be potential biomarkers for early diagnosis of PE and IUGR. It remains to be explored if early stage placentas from compromised pregnancies will have high let-7 miRNAs and will the increase in let-7 miRNAs in placenta be reflected in maternal blood. Animal models of IUGR can be used to answer these questions.