Smarca4 deficiency induces Pttg1 oncogene upregulation and hyperproliferation of tubular and interstitial cells during kidney development

Kidney formation and nephrogenesis are controlled by precise spatiotemporal gene expression programs, which are coordinately regulated by cell-cycle, cell type-specific transcription factors and epigenetic/chromatin regulators. However, the roles of epigenetic/chromatin regulators in kidney development and disease remain poorly understood. In this study, we investigated the impact of deleting the chromatin remodeling factor Smarca4 (Brg1), a human Wilms tumor-associated gene, in Wnt4-expressing cells. Smarca4 deficiency led to severe tubular defects and a shortened medulla. Through unbiased single-cell RNA sequencing analyses, we identified multiple types of Wnt4Cre-labeled interstitial cells, along with nephron-related cells. Smarca4 deficiency increased interstitial cells but markedly reduced tubular cells, resulting in cells with mixed identity and elevated expression of cell-cycle regulators and genes associated with extracellular matrix and epithelial-to-mesenchymal transition/fibrosis. We found that Smarca4 loss induced a significant upregulation of the oncogene Pttg1 and hyperproliferation of Wnt4Cre-labeled cells. These changes in the cellular state could hinder the cellular transition into characteristic tubular structures, eventually leading to fibrosis. In conclusion, our findings shed light on novel cell types and genes associated with Wnt4Cre-labeled cells and highlight the critical role of Smarca4 in regulating tubular cell differentiation and the expression of the cancer-causing gene Pttg1 in the kidney. These findings may provide valuable insights into potential therapeutic strategies for renal cell carcinoma resulting from SMARCA4 deficiency

Systems modeling of white matter microstructural abnormalities in Alzheimer's disease

INTRODUCTION: Microstructural abnormalities in white matter (WM) are often reported in Alzheimer's disease (AD). However, it is unclear which brain regions have the strongest WM changes in presymptomatic AD and what biological processes underlie WM abnormality during disease progression. METHODS: We developed a systems biology framework to integrate matched diffusion tensor imaging (DTI), genetic and transcriptomic data to investigate regional vulnerability to AD and identify genetic risk factors and gene subnetworks underlying WM abnormality in AD. RESULTS: We quantified regional WM abnormality and identified most vulnerable brain regions. A SNP rs2203712 in CELF1 was most significantly associated with several DTI-derived features in the hippocampus, the top ranked brain region. An immune response gene subnetwork in the blood was most correlated with DTI features across all the brain regions. DISCUSSION: Incorporation of image analysis with gene network analysis enhances our understanding of disease progression and facilitates identification of novel therapeutic strategies for AD

Molecular differences in brain regional vulnerability to aging between males and females

BackgroundAging-related cognitive decline is associated with brain structural changes and synaptic loss. However, the molecular mechanisms of cognitive decline during normal aging remain elusive.ResultsUsing the GTEx transcriptomic data from 13 brain regions, we identified aging-associated molecular alterations and cell-type compositions in males and females. We further constructed gene co-expression networks and identified aging-associated modules and key regulators shared by both sexes or specific to males or females. A few brain regions such as the hippocampus and the hypothalamus show specific vulnerability in males, while the cerebellar hemisphere and the anterior cingulate cortex regions manifest greater vulnerability in females than in males. Immune response genes are positively correlated with age, whereas those involved in neurogenesis are negatively correlated with age. Aging-associated genes identified in the hippocampus and the frontal cortex are significantly enriched for gene signatures implicated in Alzheimer’s disease (AD) pathogenesis. In the hippocampus, a male-specific co-expression module is driven by key synaptic signaling regulators including VSNL1, INA, CHN1 and KCNH1; while in the cortex, a female-specific module is associated with neuron projection morphogenesis, which is driven by key regulators including SRPK2, REPS2 and FXYD1. In the cerebellar hemisphere, a myelination-associated module shared by males and females is driven by key regulators such as MOG, ENPP2, MYRF, ANLN, MAG and PLP1, which have been implicated in the development of AD and other neurodegenerative diseases.ConclusionsThis integrative network biology study systematically identifies molecular signatures and networks underlying brain regional vulnerability to aging in males and females. The findings pave the way for understanding the molecular mechanisms of gender differences in developing neurodegenerative diseases such as AD

Long-term impact of the low-FODMAP diet on gastrointestinal symptoms, dietary intake, patient acceptability, and healthcare utilization in irritable bowel syndrome

Background: The low-FODMAP diet is a frequently used treatment for irritable bowel syndrome (IBS). Most research has focused on short-term FODMAP restriction; however, guidelines recommend that high-FODMAP foods are reintroduced to individual tolerance. This study aimed to assess the long-term effectiveness of the low-FODMAP diet following FODMAP reintroduction in IBS patients. Methods: Patients with IBS were prospectively recruited to a questionnaire study following completion of dietitian-led low-FODMAP education. At baseline and following FODMAP restriction (short term) only, gastrointestinal symptoms were measured as part of routine clinical care. Following FODMAP reintroduction, (long term), symptoms, dietary intake, acceptability, food-related quality of life (QOL), and healthcare utilization were assessed. Data were reported for patients who continued long-term FODMAP restriction (adapted FODMAP) and/or returned to a habitual diet (habitual). Key Results: Of 103 patients, satisfactory relief of symptoms was reported in 12% at baseline, 61% at short-term follow-up, and 57% at long-term follow-up. At long-term follow-up, 84 (82%) patients continued an ‘adapted FODMAP’ diet (total FODMAP intake mean 20.6, SD 14.9\ua0g/d) compared with 19 (18%) of patients following a ‘habitual’ diet (29.4, SD 22.9\ua0g/d, P=.039). Nutritional adequacy was not compromised for either group. The ‘adapted FODMAP’ group reported the diet cost significantly more than the ‘habitual’ group (

Revealing and avoiding bias in semantic similarity scores for protein pairs

Abstract Background Semantic similarity scores for protein pairs are widely applied in functional genomic researches for finding functional clusters of proteins, predicting protein functions and protein-protein interactions, and for identifying putative disease genes. However, because some proteins, such as those related to diseases, tend to be studied more intensively, annotations are likely to be biased, which may affect applications based on semantic similarity measures. Thus, it is necessary to evaluate the effects of the bias on semantic similarity scores between proteins and then find a method to avoid them. Results First, we evaluated 14 commonly used semantic similarity scores for protein pairs and demonstrated that they significantly correlated with the numbers of annotation terms for the proteins (also known as the protein annotation length). These results suggested that current applications of the semantic similarity scores between proteins might be unreliable. Then, to reduce this annotation bias effect, we proposed normalizing the semantic similarity scores between proteins using the power transformation of the scores. We provide evidence that this improves performance in some applications. Conclusions Current semantic similarity measures for protein pairs are highly dependent on protein annotation lengths, which are subject to biological research bias. This affects applications that are based on these semantic similarity scores, especially in clustering studies that rely on score magnitudes. The normalized scores proposed in this paper can reduce the effects of this bias to some extent.</p

Lifelong chronic psychosocial stress induces a proteomic signature of Alzheimer's disease in wildtype mice

Late onset, sporadic Alzheimer's disease (AD) accounts for the vast majority of cases. Unlike familial AD, the factors that drive the onset of sporadic AD are poorly understood, although aging and stress play a role. The early onset/severity of neuropathology observed in most genetic mouse models of AD hampers the study of the role of aging and environmental factors; thus alternate strategies are necessary to understand the contributions of these factors to sporadic AD. We demonstrate that mice acquiring a low social status (subordinate) in a lifelong chronic psychosocial stress (CPS) model, accrue widespread proteomic changes in the frontal/temporal cortex during aging. To better understand the significance of these stress-induced changes, we compared the differentially expressed proteins (DEPs) of subordinate mice to those of patients at varying stages of dementia. Sixteen and fifteen DEPs upregulated in subordinate mice were also upregulated in patients with mild cognitive impairment (MCI) and AD, respectively. Six of those upregulated proteins (CPE, ERC2, GRIN2B, SLC6A1, SYN1, WFS1) were shared by subordinate mice and patients with MCI or AD. Finally, comparison with a spatially detailed transcriptomic database revealed that the superior frontal gyrus and hippocampus had the greatest overlap between mice subjected to lifelong CPS and AD patients. Overall, most of the overlapping proteins were functionally associated with enhanced NMDA receptor mediated glutamatergic signaling, an excitotoxicity mechanism known to affect neurodegeneration. These findings support the association between stress and AD progression and provide valuable insight into potential early biomarkers and protein mediators of this relationship

Genes Dysregulated to Different Extent or Oppositely in Estrogen Receptor-Positive and Estrogen Receptor-Negative Breast Cancers

<div><p>Background</p><p>Directly comparing gene expression profiles of estrogen receptor-positive (ER+) and estrogen receptor-negative (ER−) breast cancers cannot determine whether differentially expressed genes between these two subtypes result from dysregulated expression in ER+ cancer or ER− cancer versus normal controls, and thus would miss critical information for elucidating the transcriptomic difference between the two subtypes.</p><p>Principal Findings</p><p>Using microarray datasets from TCGA, we classified the genes dysregulated in both ER+ and ER− cancers versus normal controls into two classes: (i) genes dysregulated in the same direction but to a different extent, and (ii) genes dysregulated to opposite directions, and then validated the two classes in RNA-sequencing datasets of independent cohorts. We showed that the genes dysregulated to a larger extent in ER+ cancers than in ER− cancers enriched in glycerophospholipid and polysaccharide metabolic processes, while the genes dysregulated to a larger extent in ER− cancers than in ER+ cancers enriched in cell proliferation. Phosphorylase kinase and enzymes of glycosylphosphatidylinositol (GPI) anchor biosynthesis were upregulated to a larger extent in ER+ cancers than in ER− cancers, whereas glycogen synthase and phospholipase A2 were downregulated to a larger extent in ER+ cancers than in ER− cancers. We also found that the genes oppositely dysregulated in the two subtypes significantly enriched with known cancer genes and tended to closely collaborate with the cancer genes. Furthermore, we showed the possibility that these oppositely dysregulated genes could contribute to carcinogenesis of ER+ and ER− cancers through rewiring different subpathways.</p><p>Conclusions</p><p>GPI-anchor biosynthesis and glycogenolysis were elevated and hydrolysis of phospholipids was depleted to a larger extent in ER+ cancers than in ER− cancers. Our findings indicate that the genes oppositely dysregulated in the two subtypes are potential cancer genes which could contribute to carcinogenesis of both ER+ and ER− cancers through rewiring different subpathways.</p></div

Schematic diagram of a gene dysregulated to a larger extent in ER+ (or ER−) cancer.

<p>Black line indicates average expression level of normal controls. Dysregulated directions are denoted in red arrow for upregulation and in green arrow for downregulation. The length of the arrow lines indicates dysregulated extent. (A) A gene dysregulated to a larger extent in ER+ cancer than in ER− cancer. (B) A gene dysregulated to a larger extent in ER− cancer than in ER+ cancer.</p

Downregulation of PFKP and upregulation of FBP1 contribute to ER+ breast cancers.

<p>ER+ DE genes in the pentose phosphate pathway are denoted in red for upregulation and in green for downregulation. The red frame indicates the elevated oxidative subpathway of the pentose phosphate pathway in ER+ cancers. The figure is created based on KEGG pathway hsa00030. Only a part of the pathway is shown for clarity.</p

Clinical characteristics of the samples at diagnosis.

*<p><i>p</i> denotes results of significant test for the comparison between ER+ versus ER− breast cancer by chi-square test.</p><p>RNA-seq, RNA-sequencing; PR, Progesterone Receptor; NA, Not Available; HER2, Human Epidermal Growth Factor Receptor 2.</p