PMCID string | Title string | Sentences string |
|---|---|---|
PMC11394112 | Development of New Diffuse Large B Cell Lymphoma Mouse Models | In vivo BLI was performed weekly until mice developed endpoint criteria (i.e., body condition scoring <2 or significantly high bioluminescence (BL) signals on the whole body of >1010 radiance). |
PMC11394112 | Development of New Diffuse Large B Cell Lymphoma Mouse Models | We made the region of interest (ROI) in BLI to cover the whole body to measure the total flux (photons/sec, p/s). |
PMC11394112 | Development of New Diffuse Large B Cell Lymphoma Mouse Models | Mice with no detectable signal by the fourth-week post-injection were scored ‘ungrafted’. |
PMC11394112 | Development of New Diffuse Large B Cell Lymphoma Mouse Models | All other mice were monitored for tumor growth and survival. |
PMC11394112 | Development of New Diffuse Large B Cell Lymphoma Mouse Models | BL signals in U2932-Luc cells were observed from the second-week post-injection in both NSG-IL6 and NSG-IL6/SGM3 mice (Figure 1A,B). |
PMC11394112 | Development of New Diffuse Large B Cell Lymphoma Mouse Models | As the DLBCL growth progressed, the BL signals increased, and the focal BL signal spread throughout the body. |
PMC11394112 | Development of New Diffuse Large B Cell Lymphoma Mouse Models | While the BL of VAL-Luc cells was also observed from the second-week post-injection in NSG and NSG-IL6 mice, rapid tumor progression was noticed in comparison to the U2932-Luc cells. |
PMC11394112 | Development of New Diffuse Large B Cell Lymphoma Mouse Models | Most mice (9/11 mice) exhibited a high tumor burden by 4th week (Figure 1C,D). |
PMC11394112 | Development of New Diffuse Large B Cell Lymphoma Mouse Models | Of note, in further contrast to the U2932-Luc cells, there was no detectable engraftment of VAL-Luc cells in NSG-IL6/SGM3 mice despite some proliferation of cells near the injection site in weeks 6 and 7 (Figure 1C,D). |
PMC11394112 | Development of New Diffuse Large B Cell Lymphoma Mouse Models | These data suggest that the NSG-IL6 mice are highly permissive to both ABC and GCB subtypes of DLBCL cell lines. |
PMC11394112 | Development of New Diffuse Large B Cell Lymphoma Mouse Models | Furthermore, no engraftment for either U2932 or VAL cells was found in the NSG-SGM3 mouse strain (Figure 1A,C). |
PMC11394112 | Development of New Diffuse Large B Cell Lymphoma Mouse Models | In U2932-Luc cell-injected NSG mice, BL signals were shown in some mice (15/30 mice), whereas tumor growth in VAL-Luc-injected NSG mice rapidly progressed, and all the mice died by the 3rd week (Figure 1A,C). |
PMC11394112 | Development of New Diffuse Large B Cell Lymphoma Mouse Models | The rapid disease progression of VAL-Luc NSG-IL6-xenografted mice relative to the U2932-Luc NSG-IL6-xenografted mice corresponded to a poorer survival (Figure 2A; p = 0.0001; median survival 24 days vs. 49 days). |
PMC11394112 | Development of New Diffuse Large B Cell Lymphoma Mouse Models | We also observed a 75% (15/20) engraftment rate for U2932-Luc cells in NSG-IL6 mice and 32% (6/19) in NSG-IL6/SGM3 mice compared to 82% (9/11) for VAL-Luc cell engraftment in NSG-IL6 mice and 0% (0/10) in NSG-IL6/SGM3 mice (Figure 2B,C). |
PMC11394112 | Development of New Diffuse Large B Cell Lymphoma Mouse Models | Of note, both DLBCL cell lines in NSG-IL6 mice demonstrated uniform progression to death in the late phase of the disease. |
PMC11394112 | Development of New Diffuse Large B Cell Lymphoma Mouse Models | All mice injected with U2932-Luc and VAL-Luc died in a 16- and 9-day window, respectively. |
PMC11394112 | Development of New Diffuse Large B Cell Lymphoma Mouse Models | Previously, the subcutaneous passaged WSU in NOD/-scid mice demonstrated lymph node infiltration . |
PMC11394112 | Development of New Diffuse Large B Cell Lymphoma Mouse Models | U2932 and primary DLBCL cells in the MISTRG mice engrafted with cord blood human hematopoietic stem (HSC) cells or non-engrafted MISTRG6 showed spleen infiltration . |
PMC11394112 | Development of New Diffuse Large B Cell Lymphoma Mouse Models | To assess organ-specific engraftment of DLBCL cells in NSG-IL6 mice, we euthanized four xenografted mice per week at weeks 2–6 post-injection and performed ex vivo imaging of the excised organs. |
PMC11394112 | Development of New Diffuse Large B Cell Lymphoma Mouse Models | U2932-Luc cells were initially found in the spleen, liver, and lungs starting in week 2 (Figure 3A,B, left panels). |
PMC11394112 | Development of New Diffuse Large B Cell Lymphoma Mouse Models | Subsequently, U2932 cells were found in the ovaries of female mice, which is reflective of the parental tumor , spine, and brain (Supplementary Figure S1). |
PMC11394112 | Development of New Diffuse Large B Cell Lymphoma Mouse Models | VAL-Luc cells also showed a similar pattern but occurred earlier (Figure 3D,E, right panels). |
PMC11394112 | Development of New Diffuse Large B Cell Lymphoma Mouse Models | Both U2932-Luc and VAL-Luc cells in NSG-IL6 mice exhibited a highly uniform tissue tropism that was unique to each cell line (spleen > liver > lung > brain > ovary). |
PMC11394112 | Development of New Diffuse Large B Cell Lymphoma Mouse Models | Next, we confirmed U2932-Luc and VAL-Luc infiltrations into the initially targeted organs and spleen, liver, and lung tissues by immunohistochemistry (IHC) staining for the human CD20 B cell surface marker. |
PMC11394112 | Development of New Diffuse Large B Cell Lymphoma Mouse Models | IHC staining showed a low CD20 positive cell infiltrate at the second-week post-injection that steadily increased at the third- and fourth-week post-injection (Figure 3C,F), consistent with the BL imaging (Figure 1 and Figure 3A,D). |
PMC11394112 | Development of New Diffuse Large B Cell Lymphoma Mouse Models | Notably, the NSG-IL6 mouse spleens at week 4 were dominated by the U2932-Luc cells. |
PMC11394112 | Development of New Diffuse Large B Cell Lymphoma Mouse Models | These findings confirm the early and highly permissive IL6-expressing mice for the engraftment and growth of DLBCL cells in organs consistent with clinical disease progression. |
PMC11394112 | Development of New Diffuse Large B Cell Lymphoma Mouse Models | To confirm evidence that IL6 signaling is a critical driver of a subset of DLBCL and an indicator of engraftment and growth in NSG-IL6 mice , we treated U2932 and VAL cells with human IL6 and determined STAT3 activation. |
PMC11394112 | Development of New Diffuse Large B Cell Lymphoma Mouse Models | We observed STAT3 activation in U2932 cells after 1 h incubation with human IL6, in agreement with the previous report, and further showed that phosphorylation of STAT3 (pSTAT3) is inducible at a higher abundance after 30 min (Figure 4A). |
PMC11394112 | Development of New Diffuse Large B Cell Lymphoma Mouse Models | Although VAL cells show the constitutive activation of STAT3 as indicated by the presence of pSTAT3 in untreated cells, IL6 promotes additional STAT3 activation by ~6-fold after 30 min and to a lesser extent after 1 h. Previous work linked the expression of the IL6 receptor (IL6R) α subunit (IL6Rα) and gp130, the signaling chain subunit of the IL6R, to IL6-mediated STAT3 activation in DLBCL . |
PMC11394112 | Development of New Diffuse Large B Cell Lymphoma Mouse Models | We confirmed that both IL6Rα and gp130 are expressed in U2932 and VAL cells, and we interestingly found VAL cells to express a significantly higher abundance of both subunits (Supplementary Figure S2). |
PMC11394112 | Development of New Diffuse Large B Cell Lymphoma Mouse Models | While human IL6 did not significantly increase U2932 cell proliferation, human IL6 increased VAL cell proliferation (Figure 4B), supporting the enhanced growth of VAL-Luc cells engrafted in NSG-IL6 mice compared to U2932-Luc cells. |
PMC11394112 | Development of New Diffuse Large B Cell Lymphoma Mouse Models | However, the basal proliferation of VAL cells compared to U2932 cells was significantly higher (p = 0.01, area under the curve), most likely owing to the aggressive proliferative phenotype associated with the so-called double- or triple-hit (BCL2/BCL6/MYC translocation, ) positive VAL cells, and thus, it also contributes to the more rapid expansion in NSG-IL6 mice. |
PMC11394112 | Development of New Diffuse Large B Cell Lymphoma Mouse Models | We developed a humanized mouse model that supports DLBCL engraftment and expansion in secondary lymphoid organs and extranodal sites (e.g., liver and lung) consistent with clinical presentation and further confirmed the pivotal role of human IL6 in human DLBCL cell homing in mice. |
PMC11394112 | Development of New Diffuse Large B Cell Lymphoma Mouse Models | A previous study demonstrated that ABC DLBCL cell lines engrafted and colonized the bone marrow and spleen only when MISTRG was engrafted with human HSCs or human IL6 was expressed in MISTRG (MISTRG6) . |
PMC11394112 | Development of New Diffuse Large B Cell Lymphoma Mouse Models | These data suggest that human IL6 provides a more fertile environment for DLBCL cells, particularly subsets with inherent responsiveness to IL6 signaling, to engraft and expand in an in vivo model. |
PMC11394112 | Development of New Diffuse Large B Cell Lymphoma Mouse Models | However, it raises another question whether human IL6 alone is sufficient for the homing of human DLBCL cells in immune-deficient mice. |
PMC11394112 | Development of New Diffuse Large B Cell Lymphoma Mouse Models | Here, we evaluated DLBCL colonization and expansion in NSG mice expressing human IL3, CSF2, and KITLG with and without human IL6 co-expression and also in IL6-only-expressing NSG mice. |
PMC11394112 | Development of New Diffuse Large B Cell Lymphoma Mouse Models | Our in vivo studies show that human IL6-alone-expressing NSG mice are permissive to the engraftment and organ colonization of the U2932 ABC and VAL GCB DLBCL cells, strongly indicating that IL6 is sufficient for systemic DLBCL tumor growth. |
PMC11394112 | Development of New Diffuse Large B Cell Lymphoma Mouse Models | Unlike MISTRG, a similar mouse, NSG-SGM3 mice, exhibited no engraftment of either ABC or GCB cells, whereas in the case of the NSG-alone engraftment of ABC cells was poor (50%), while GCB cell engraftment was rapid and vigorous. |
PMC11394112 | Development of New Diffuse Large B Cell Lymphoma Mouse Models | Such discrepancy may be derived from differences of other human cytokines or mouse backgrounds. |
PMC11394112 | Development of New Diffuse Large B Cell Lymphoma Mouse Models | However, without engraftment success rates in MISTRG or MISTRG6, we could not explain such a difference. |
PMC11394112 | Development of New Diffuse Large B Cell Lymphoma Mouse Models | Of interest, the NSG-IL6/SGM3 mice were somewhat permissive to U2932 engraftment (32%) and steadily increased tumor burden, leading to worsening survival. |
PMC11394112 | Development of New Diffuse Large B Cell Lymphoma Mouse Models | Although traditional subcutaneous xenograft DLBCL mouse models allow for adequate drug discovery studies, the major limitation is the localized tumor growth in an often clinically non-relevant tissue that constrains the translation of how effectively new therapeutic strategies control tumor burden in humans. |
PMC11394112 | Development of New Diffuse Large B Cell Lymphoma Mouse Models | An in vivo model that more closely recapitulates the clinical progression of DLBCL within tissues that parallel the human disease provides a substantial advantage over these models. |
PMC11394112 | Development of New Diffuse Large B Cell Lymphoma Mouse Models | While spontaneous mouse lymphoma models overcome this limitation, these mouse tumors typically take months to develop and are driven by the enforced expression of specific oncogenes that fail to represent the molecular heterogeneity of DLBCL between subtypes and within a given tumor. |
PMC11394112 | Development of New Diffuse Large B Cell Lymphoma Mouse Models | Our approach of an intravenous injection of Luciferase-expressing human DLBCL cells in human IL6 transgenic NSG mice demonstrated rapid tumor cell engraftment and expansion, showing unique organ infiltration patterns reflecting the DLBCL subtype. |
PMC11394112 | Development of New Diffuse Large B Cell Lymphoma Mouse Models | We observed DLBCL cell infiltration and growth as early as two weeks post-injection, significantly faster than the MISTRG6 model . |
PMC11394112 | Development of New Diffuse Large B Cell Lymphoma Mouse Models | Furthermore, despite the previous survey of GCB DLBCL cell lines demonstrating this subtype displays little to no IL6R expression, we show the VAL GCB DLBCL cells express a high abundance of both IL6R subunits. |
PMC11394112 | Development of New Diffuse Large B Cell Lymphoma Mouse Models | This finding suggests that not all GCB DLBCL cells are deficient in IL6 signaling and perhaps supports yet another aggressive phenotype of the double- or triple-hit DLBCL subset. |
PMC11394112 | Development of New Diffuse Large B Cell Lymphoma Mouse Models | In summary, we establish an intravenous xenograft model for DLBCL that shortens the time to tumor development (median survival of U2932-Luc and VAL-Luc in NSG-IL6 mice; 49 days and 24 days), shows highly uniform tumor progression, follows a clinical progression of the disease, and requires minimal genetic alterations in mice with high potential to advance the preclinical testing of new therapeutics. |
PMC12267437 | Identification of functional non-coding variants associated with orofacial cleft | Oral facial cleft (OFC) comprises cleft lip with or without cleft palate (CL/P) or cleft palate only. |
PMC12267437 | Identification of functional non-coding variants associated with orofacial cleft | Genome wide association studies (GWAS) of isolated OFC have identified common single nucleotide polymorphisms (SNPs) in many genomic loci where the presumed effector gene (for example, IRF6 in the 1q32 locus) is expressed in embryonic oral epithelium. |
PMC12267437 | Identification of functional non-coding variants associated with orofacial cleft | To identify candidates for functional SNPs at eight such loci we conduct a massively parallel reporter assay in a fetal oral epithelial cell line, revealing SNPs with allele-specific effects on enhancer activity. |
PMC12267437 | Identification of functional non-coding variants associated with orofacial cleft | We filter these SNPs against chromatin-mark evidence of enhancers and test a subset in traditional reporter assays, which support the candidacy of SNPs at loci containing FOXE1, IRF6, MAFB, TFAP2A, and TP63. |
PMC12267437 | Identification of functional non-coding variants associated with orofacial cleft | For two SNPs near IRF6 and one near FOXE1, we engineer the genome of induced pluripotent stem cells, differentiate the cells into embryonic oral epithelium, and discover allele-specific effects on the levels of effector gene expression, and, in two cases, the binding affinity of transcription factors FOXE1 or ETS2. |
PMC12267437 | Identification of functional non-coding variants associated with orofacial cleft | Conditional analyses of GWAS data suggest the two functional SNPs near IRF6 account for the majority of risk for CL/P at this locus. |
PMC12267437 | Identification of functional non-coding variants associated with orofacial cleft | This study connects genetic variation associated with OFC to mechanisms of pathogenesis. |
PMC12267437 | Identification of functional non-coding variants associated with orofacial cleft | Oral facial cleft (OFC) is a multifactorial disorder that can present as a cleft lip with or without cleft palate (CL/P) or a cleft palate only (CP) and has a genetic predisposition. |
PMC12267437 | Identification of functional non-coding variants associated with orofacial cleft | More than one hundred syndromes include OFC as a phenotype, and overall, about 30% of CL/P cases are syndromic. |
PMC12267437 | Identification of functional non-coding variants associated with orofacial cleft | Such syndromes are generally caused by mutations in single genes and follow a Mendelian inheritance pattern. |
PMC12267437 | Identification of functional non-coding variants associated with orofacial cleft | The remaining cases are non-syndromic or isolated. |
PMC12267437 | Identification of functional non-coding variants associated with orofacial cleft | The etiology of non-syndromic OFC is partially genetic, as the concordance of non-syndromic OFC is 50% in identical twins but just 3–5% in other first-degree relatives. |
PMC12267437 | Identification of functional non-coding variants associated with orofacial cleft | Multiple independent genome-wide association studies (GWAS), and meta-analyses thereof, have identified more than 40 loci where alleles of common single-nucleotide polymorphisms (SNPs) are over-represented in cases versus in controls with the same ancestry (reviewed in ref. ). |
PMC12267437 | Identification of functional non-coding variants associated with orofacial cleft | Importantly, however, most of the heritable risk for isolated OFC has not been assigned to any gene or locus. |
PMC12267437 | Identification of functional non-coding variants associated with orofacial cleft | Moreover, GWAS results alone do not illuminate the mechanisms of pathogenesis attributable to genetic variation at each locus. |
PMC12267437 | Identification of functional non-coding variants associated with orofacial cleft | Understanding these mechanisms may point to additional genes in which mutations will contribute risk for non-syndromic OFC and may guide the design of preventative therapies. |
PMC12267437 | Identification of functional non-coding variants associated with orofacial cleft | Identifying functional (causal) SNPs among those in linkage disequilibrium with them is challenging. |
PMC12267437 | Identification of functional non-coding variants associated with orofacial cleft | Most SNPs lie in non-coding DNA, and the functional subset of them presumably disrupt cis-regulatory sequences (i.e., enhancers and promoters). |
PMC12267437 | Identification of functional non-coding variants associated with orofacial cleft | However, the sequence constraints of cis-regulatory sequences remain poorly understood. |
PMC12267437 | Identification of functional non-coding variants associated with orofacial cleft | We and others have used machine learning to mine sets of tissue-specific enhancers for sequence patterns, and there are in silico tools for inferring variants that affect enhancer function, but currently there is no tool that can robustly identify non-coding variants that alter enhancer activity. |
PMC12267437 | Identification of functional non-coding variants associated with orofacial cleft | An alternative approach is the massively parallel reporter assay (MPRA). |
PMC12267437 | Identification of functional non-coding variants associated with orofacial cleft | MPRAs have been widely used to detect elements with enhancer activity, and in some cases to detect the effect of variants on enhancer activity. |
PMC12267437 | Identification of functional non-coding variants associated with orofacial cleft | A challenge in deploying MPRA to identify functional SNPs is that, because the results are dependent on the cellular context, it may be necessary to use a cell line that models the embryonic cell type in which the SNPs affect disease risk. |
PMC12267437 | Identification of functional non-coding variants associated with orofacial cleft | The 1q32/IRF6 locus is associated with OFC in multiple ethnic groups. |
PMC12267437 | Identification of functional non-coding variants associated with orofacial cleft | IRF6, encoding the transcription factor Interferon Regulatory Factor 6, is strong candidate for the risk-relevant gene (i.e., the effector gene) in this locus because mutations in IRF6 are found in about 70% of patients with Van der Woude syndrome, the most common syndromic form of OFC (VWS1, OMIM # 119300). |
PMC12267437 | Identification of functional non-coding variants associated with orofacial cleft | Finding the functional SNPs at this locus would yield insight into the regulation of IRF6 gene expression during morphogenesis of the face and, if the transcription factors whose binding is affected by those SNPs are identified, would identify new candidate genes for OFC. |
PMC12267437 | Identification of functional non-coding variants associated with orofacial cleft | However, a meta-analysis of several GWAS identified more than 600 SNPs at this locus with P values indicating at least a suggestive association with OFC. |
PMC12267437 | Identification of functional non-coding variants associated with orofacial cleft | One of these SNPs, rs642961, resides in an enhancer of IRF6 and alters the binding of the transcription factor AP2-α (TFAP2A) in an electrophoretic mobility shift assay, suggesting it is functional. |
PMC12267437 | Identification of functional non-coding variants associated with orofacial cleft | However, this conclusion is uncertain because this SNP did not have allele-specific effects in a standard reporter assay or in an MPRA. |
PMC12267437 | Identification of functional non-coding variants associated with orofacial cleft | The large number of OFC-associated SNPs at this locus, and others, makes it difficult to determine which are functional. |
PMC12267437 | Identification of functional non-coding variants associated with orofacial cleft | Here, we deployed an MPRA in a fetal oral epithelium cell line to nominate candidate functional SNPs among those associated with OFC and within loci where the presumed effector gene is expressed in oral epithelium. |
PMC12267437 | Identification of functional non-coding variants associated with orofacial cleft | We validated a subset of the MPRA results using traditional luciferase reporter assays in the cell line and in primary keratinocytes. |
PMC12267437 | Identification of functional non-coding variants associated with orofacial cleft | For two promising SNPs near IRF6 and one near FOXE1, we engineered the genotype of the SNPs in induced pluripotent stem cells, differentiated the cells into embryonic oral epithelium, and then assessed allele-specific effects on gene expression and transcription factor binding. |
PMC12267437 | Identification of functional non-coding variants associated with orofacial cleft | These studies support six SNPs as being functional, with varying levels of support, and two of these SNPs as accounting for most of the heritable risk for CL/P phenotype attributed to the IRF6 locus in the cohort analyzed here. |
PMC12267437 | Identification of functional non-coding variants associated with orofacial cleft | For analysis by MPRA, we picked 887 SNPs from eight loci associated with OFC and in which the currently presumed effector gene is expressed in oral epithelium, although not necessarily only there, and which regulates differentiation of an epithelial tissue (1q32/IRF6, 2p21/THADA, 3q28/TP63, 6p24.3/TFAP2A, 9q22.2/GADD45G, 9q22.33/FOXE1, 12q13.13/KRT18, and 20q12/MAFB) (Table 1 and Supplementary Data 1, 2). |
PMC12267437 | Identification of functional non-coding variants associated with orofacial cleft | At seven of the loci, we picked SNPs based on their significance in a genome-wide meta-analysis of two prior OFC studies (Table 1 and Supplementary Data 2). |
PMC12267437 | Identification of functional non-coding variants associated with orofacial cleft | We additionally included SNPs at the TFAP2A locus identified in an independent GWAS of CL/P in Han Chinese. |
PMC12267437 | Identification of functional non-coding variants associated with orofacial cleft | At an eighth locus (9q22.33/FOXE1), we picked SNPs in strong linkage disequilibrium with the GWAS lead SNP (rs12347191) and annotated as being within regulatory elements (Table 1 and Supplementary Data 2). |
PMC12267437 | Identification of functional non-coding variants associated with orofacial cleft | As outlined in Fig. 1a, we synthesized a library of reporter plasmids containing 161 base-pairs (bp) genomic test elements each centered on an OFC-associated SNP; OFC risk and non-risk alleles of each SNP were represented in four replicate constructs with distinct barcodes (Supplementary Data 3, 4). |
PMC12267437 | Identification of functional non-coding variants associated with orofacial cleft | We performed the MPRA in GMSM-K cells (Supplementary Data 5), a cell line derived from human fetal oral mucosa. |
PMC12267437 | Identification of functional non-coding variants associated with orofacial cleft | The results were strongly correlated (R ≥ 0.876) across four replicate experiments (Supplementary Fig. 1a).Fig. |
PMC12267437 | Identification of functional non-coding variants associated with orofacial cleft | 1MPRA identified SNPs with allele-specific significant effects on reporter activity.a Schematic of MPRA library construction and execution. |
PMC12267437 | Identification of functional non-coding variants associated with orofacial cleft | BC, barcode. |
PMC12267437 | Identification of functional non-coding variants associated with orofacial cleft | Yellow and red asterisks: non-risk and risk allele, respectively. |
PMC12267437 | Identification of functional non-coding variants associated with orofacial cleft | b Scatter dot plot showing (black dots) 65 SNPs with significant allele-specific effects on reporter activity in the MPRA and (gray dots) 822 SNPs without them. |
PMC12267437 | Identification of functional non-coding variants associated with orofacial cleft | Arrows indicate the functional SNPs identified in this study (two near IRF6, rs11119348 and rs661849, and one near FOXE1, rs10984103). |
PMC12267437 | Identification of functional non-coding variants associated with orofacial cleft | Dashed lines indicate the 95th percentile of the reporter activity of scrambled elements; on both axes, zero, i.e., log2(1) represents the reporter activity of the empty vector. |
PMC12267437 | Identification of functional non-coding variants associated with orofacial cleft | Table 1The number of SNPs tested, and the number with allele-specific effects, in the MPRA at each locusLocusTested in MPRA (887 total)Allele-specific effects in MPRA (65 total)Further supported by chromatin evidence in embryonic faces and/or NHEKTested in luciferase reporter assays in HEKn and GMSM-KTested by genome engineering in induced oral epithelium1q32/IRF6608469rs11119348, rs661849rs11119348, rs6618492p21/THADA401-3q28/TP631411rs754368776p24.3/TFAP2A11282rs2012659q22.2/GADD45G362-9q22.33/FOXE1911rs10984103rs1098410312q13.13/KRT18142-20q12/MAFB5441rs4812449 a Schematic of MPRA library construction and execution. |
PMC12267437 | Identification of functional non-coding variants associated with orofacial cleft | BC, barcode. |
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