The biogenesis of ribosomes in vivo is an essential process for cellular functions. Transcription of ribosomal RNA (rRNA) genes is the rate-limiting step in ribosome biogenesis controlled by environmental conditions. Here, we investigated the role of folate antagonist on changes of DNA double-strand breaks (DSBs) landscape in mouse embryonic stem cells. A significant DSB enhancement was detected in the genome of these cells and a large majority of these DSBs were found in rRNA genes. Furthermore, spontaneous DSBs in cells under folate deficiency conditions were located exclusively within the rRNA gene units, representing a H3K4me1 hallmark. Enrichment H3K4me1 at the hot spots of DSB regions enhanced the recruitment of upstream binding factor (UBF) to rRNA genes, resulting in the increment of rRNA genes transcription. Supplement of folate resulted in a restored UBF binding across DNA breakage sites of rRNA genes, and normal rRNA gene transcription. In samples from neural tube defects (NTDs) with low folate level, up-regulation of rRNA gene transcription was observed, along with aberrant UBF level. Our results present a new view by which alterations in folate levels affects DNA breakage through epigenetic control leading to the regulation of rRNA gene transcription during the early stage of development.
Wnt signaling plays a major role in early neural development. An aberrant activation in Wnt/β-catenin pathway causes defective anteroposterior patterning, which results in neural tube closure defects (NTDs). Changes in folate metabolism may participate in early embryo fate determination. We have identified that folate deficiency activated Wnt/β-catenin pathway by upregulating a chorion-specific transcription factor Gcm1. Specifically, folate deficiency promoted formation of the Gcm1/β-catenin/T-cell factor (TCF4) complex formation to regulate the Wnt targeted gene transactivation through Wnt-responsive elements. Moreover, the transcription factor Nanog upregulated Gcm1 transcription in mESCs under folate deficiency. Lastly, in NTDs mouse models and low-folate NTDs human brain samples, Gcm1 and Wnt/β-catenin targeted genes related to neural tube closure are specifically overexpressed. These results indicated that low-folate level promoted Wnt/β-catenin signaling via activating Gcm1, and thus leaded into aberrant vertebrate neural development.
BackgroundAn accurate and noninvasive method is of great importance to assess angiogenesis and cellularity of bone marrow in acute leukemia (AL).PurposeTo investigate whether the intravoxel incoherent motion (IVIM) parameters correlate with the histological characteristics of infiltrated marrow in AL patients and compare the difference between acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML).Study TypeProspective.Population ModelForty newly diagnosed patients with AL, including 20 AML and 20 ALL.Field Strength/Sequence1.5T/T1WI and IVIM.AssessmentIVIM‐derived parameters (true diffusion coefficient D, pseudodiffusion coefficient D*, and perfusion fraction, f) were measured in lumbar marrow. Histopathological analyses were performed from samples of marrow biopsy.Statistical TestsThe correlations between IVIM parameters and histological parameters used the Spearman correlation test. The difference of IVIM parameters and histological parameters between ALL and AML groups used the unpaired t‐test or Mann–Whitney U‐test, as appropriate.ResultsThe f was positively correlated with microvessel density (MVD) in patients with ALL, AML, and AL (r = 0.740, P = 0.006; r = 0.771, P < 0.001; and r = 0.750, P < 0.001, respectively). There were no significant correlations between D and bone marrow cellularity in the three groups (r = –0.289, P = 0.362; r = 0.281, P = 0.292; and r = 0.058, P = 0.769, respectively). D and f values of ALL were higher than that of AML group (t = 3.332, P = 0.003 and t = 2.600, P = 0.014, respectively). MVD was higher in ALL than AML (t = 2.120, P = 0.044), whereas bone marrow cellularity had no significant difference between AML and ALL (t = –0.682, P = 0.501).Data ConclusionThe f value derived from IVIM in bone marrow was positively correlated with MVD, while f might be able to show a difference of vascularity between ALL and AML. Therefore, the f value can be used as an alternative imaging marker of angiogenesis in marrow of AL patients.Level of Evidence: 1Technical Efficacy Stage: 3J. Magn. Reson. Imaging 2020;51:1720–1726.
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