Putative role of CG3160 in morphogen secretion

Morphogens are secreted molecules that influence the fate of neighboring cells in a concentration-dependant manner. For this reason, their distribution and diffusion strongly influence their roles. In my master thesis, I focused on a posttranslational modification that might be involved in the diffusion of morphogens: GPI-anchoring. This mechanism links a target protein to a phosphatidylinositol via sugar moieties, thereby anchoring the protein to the cell membrane. To study the putative involvement of GPI-anchors in morphogen distribution, a gene implicated in the GPI-attachment process was used as a tool (CG3160). It was cloned and over expressed in cell culture and in flies to study the putative modification induced on morphogen diffusion. We found in cell culture that this over expression leads to an increased secretion of Wingless, a well-known morphogen in flies. In Vivo, wing imaginal disc were used to observe Wingless distribution when CG3160 is over expressed. No modification could be detected directly on this morphogen, but the activation of one of its target gene, sensless, was reduced. The results obtained are not sufficient to affirm that Wingless is a GPI-attached protein. Nevertheless, they show that CG3160 plays a role in Wg secretion, and that this role is important for sensless activation

Total knee arthroplasty in achondroplasia without deformity correction: A case report with 11 years' follow-up

Knee osteoarthritis in patients with achondroplasia is rare. Bowleg deformity is typical but corrective surgery is limited. Thus, primary total knee arthroplasty (TKA) might be challenging due to the particular anatomy. We report on a patient with 11 year's follow-up after a TKA performed maintaining bowleg alignment, using a posterior stabilized, fixed-bearing design. Sequential X-rays showed radiolucencies on the femoral component within two years postoperatively, slightly increasing over time but stable at last follow-up. The Oxford Knee Score showed an excellent result at 11 years. Despite the peculiarities of a case report, TKA without concomitant osteotomies might be an option for such patients. Nevertheless, a thorough discussion about pros and cons is paramount

Data from: Identification of ZEB1 as a central component of the adipogenic gene regulatory network

Adipose tissue is a key determinant of whole body metabolism and energy homeostasis. Unraveling the regulatory mechanisms underlying adipogenesis is therefore highly relevant from a biomedical perspective. Our current understanding of fat cell differentiation is centered on the transcriptional cascades driven by the C/EBP protein family and the master regulator PPARγ. To elucidate further components of the adipogenic gene regulatory network, we performed a large-scale transcription factor (TF) screen overexpressing 734 TFs in mouse pre-adipocytes and probed their effect on differentiation. We identified 23 novel pro-adipogenic TFs and characterized the top ranking TF, ZEB1, as being essential for adipogenesis both in vitro and in vivo. Moreover, its expression levels correlate with fat cell differentiation potential in humans. Genomic profiling further revealed that this TF directly targets and controls the expression of most early and late adipogenic regulators, identifying ZEB1 as a central transcriptional component of fat cell differentiation

Table S1 - TF_screen

Percentage differentiated 3T3-L1 cells in response to transcription factor overexpression

Population Variation and Genetic Control of Modular Chromatin Architecture in Humans

Chromatin state variation at gene regulatory elements is abundant across individuals, yet we understand little about the genetic basis of this variability. Here, we profiled several histone modifications, the transcription factor (TF) PU.1, RNA polymerase II, and gene expression in lymphoblastoid cell lines from 47 whole-genome sequenced individuals. We observed that distinct cis-regulatory elements exhibit coordinated chromatin variation across individuals in the form of variable chromatin modules (VCMs) at sub-Mb scale. VCMs were associated with thousands of genes and preferentially cluster within chromosomal contact domains. We mapped strong proximal and weak, yet more ubiquitous, distal-acting chromatin quantitative trait loci (cQTL) that frequently explain this variation. cQTLs were associated with molecular activity at clusters of cis-regulatory elements and mapped preferentially within TF-bound regions. We propose that local, sequence-independent chromatin variation emerges as a result of genetic perturbations in cooperative interactions between cis-regulatory elements that are located within the same genomic domain

Coordinated effects of sequence variation on DNA binding, chromatin structure, and transcription

DNA sequence variation has been associated with quantitative changes in molecular phenotypes such as gene expression, but its impact on chromatin states is poorly characterized. To understand the interplay between chromatin and genetic control of gene regulation, we quantified allelic variability in transcription factor binding, histone modifications, and gene expression within humans. We found abundant allelic specificity in chromatin and extensive local, short-range, and long-range allelic coordination among the studied molecular phenotypes. We observed genetic influence on most of these phenotypes, with histone modifications exhibiting strong context-dependent behavior. Our results implicate transcription factors as primary mediators of sequence-specific regulation of gene expression programs, with histone modifications frequently reflecting the primary regulatory event

Population Variation and Genetic Control of Modular Chromatin Architecture in Humans Article Population Variation and Genetic Control of Modular Chromatin Architecture in Humans

Graphical Abstract Highlights SUMMARY Chromatin state variation at gene regulatory elements is abundant across individuals, yet we understand little about the genetic basis of this variability. Here, we profiled several histone modifications, the transcription factor (TF) PU.1, RNA polymerase II, and gene expression in lymphoblastoid cell lines from 47 whole-genome sequenced individuals. We observed that distinct cis-regulatory elements exhibit coordinated chromatin variation across individuals in the form of variable chromatin modules (VCMs) at sub-Mb scale. VCMs were associated with thousands of genes and preferentially cluster within chromosomal contact domains. We mapped strong proximal and weak, yet more ubiquitous, distal-acting chromatin quantitative trait loci (cQTL) that frequently explain this variation. cQTLs were associated with molecular activity at clusters of cis-regulatory elements and mapped preferentially within TF-bound regions. We propose that local, sequence-independent chromatin variation emerges as a result of genetic perturbations in cooperative interactions between cis-regulatory elements that are located within the same genomic domain