List of publications for the week of April 26, 2021
In vivo evaluation of heme and non-heme iron content and neuronal density in human basal ganglia (2021) NeuroImage, 235, art. no. 118012, .
Yablonskiy, D.A.a , Wen, J.b , Kothapalli, S.V.V.N.a , Sukstanskii, A.L.a
a Department of Radiology, Washington University in St. Louis, 4525 Scott Ave. Room 3216, St. Louis, MO 63110, United States
b Department of Radiology, The First Affiliated Hospital of USTC, Hefei, Anhui 230001, China
Non-heme iron is an important element supporting the structure and functioning of biological tissues. Imbalance in non-heme iron can lead to different neurological disorders. Several MRI approaches have been developed for iron quantification relying either on the relaxation properties of MRI signal or measuring tissue magnetic susceptibility. Specific quantification of the non-heme iron can, however, be constrained by the presence of the heme iron in the deoxygenated blood and contribution of cellular composition. The goal of this paper is to introduce theoretical background and experimental MRI method allowing disentangling contributions of heme and non-heme irons simultaneously with evaluation of tissue neuronal density in the iron-rich basal ganglia. Our approach is based on the quantitative Gradient Recalled Echo (qGRE) MRI technique that allows separation of the total R2* metric characterizing decay of GRE signal into tissue-specific (R2t) and the baseline blood oxygen level-dependent (BOLD) contributions. A combination with the QSM data (also available from the qGRE signal phase) allowed further separation of the tissue-specific R2t metric in a cell-specific and non-heme-iron-specific contributions. It is shown that the non-heme iron contribution to R2t* relaxation can be described with the previously developed Gaussian Phase Approximation (GPA) approach. qGRE data were obtained from 22 healthy control participants (ages 26–63 years). Results suggest that the ferritin complexes are aggregated in clusters with an average radius about 100nm comprising approximately 2600 individual ferritin units. It is also demonstrated that the concentrations of heme and non-heme iron tend to increase with age. The strongest age effect was seen in the pallidum region, where the highest age-related non-heme iron accumulation was observed. © 2021 The Authors
BOLD; Brain iron; Neuronal density; QSM; Quantitative gradient recalled echo MRI; R2; R2t
National Institutes of HealthNIH20140257, R01AG054513
Document Type: Article
Publication Stage: Final
Brd4-bound enhancers drive cell-intrinsic sex differences in glioblastoma
(2021) Proceedings of the National Academy of Sciences of the United States of America, 118 (16), .
Kfoury, N.a b , Qi, Z.c d , Prager, B.C.e f , Wilkinson, M.N.c d , Broestl, L.a g , Berrett, K.C.h , Moudgil, A.c d g , Sankararaman, S.c d , Chen, X.c d , Gertz, J.h , Rich, J.N.e i , Mitra, R.D.d j , Rubin, J.B.k l
a Department of Pediatrics, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110
b Department of Neurological Surgery, University of California San Diego, La Jolla, CA, 92037, Italy
c Department of Genetics, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110
d Center for Genome Sciences and Systems Biology, Washington University in St. Louis, St. Louis, MO 63110
e Division of Regenerative Medicine, Department of Medicine, University of California San Diego, La Jolla, CA, 92037, Italy
f Cleveland Clinic Lerner College of Medicine, Cleveland, OH 44195
g Medical Scientist Training Program, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110
h Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, United States
i Department of Neurosciences, University of California San Diego, La Jolla, CA, 92037, Italy
j Department of Genetics, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110; Rubin_J@kids.wustl.edu
k Department of Pediatrics, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110; firstname.lastname@example.org Rubin_J@kids.wustl.edu
l Department of Neuroscience, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110
Sex can be an important determinant of cancer phenotype, and exploring sex-biased tumor biology holds promise for identifying novel therapeutic targets and new approaches to cancer treatment. In an established isogenic murine model of glioblastoma (GBM), we discovered correlated transcriptome-wide sex differences in gene expression, H3K27ac marks, large Brd4-bound enhancer usage, and Brd4 localization to Myc and p53 genomic binding sites. These sex-biased gene expression patterns were also evident in human glioblastoma stem cells (GSCs). These observations led us to hypothesize that Brd4-bound enhancers might underlie sex differences in stem cell function and tumorigenicity in GBM. We found that male and female GBM cells exhibited sex-specific responses to pharmacological or genetic inhibition of Brd4. Brd4 knockdown or pharmacologic inhibition decreased male GBM cell clonogenicity and in vivo tumorigenesis while increasing both in female GBM cells. These results were validated in male and female patient-derived GBM cell lines. Furthermore, analysis of the Cancer Therapeutic Response Portal of human GBM samples segregated by sex revealed that male GBM cells are significantly more sensitive to BET (bromodomain and extraterminal) inhibitors than are female cells. Thus, Brd4 activity is revealed to drive sex differences in stem cell and tumorigenic phenotypes, which can be abrogated by sex-specific responses to BET inhibition. This has important implications for the clinical evaluation and use of BET inhibitors. Copyright © 2021 the Author(s). Published by PNAS.
BET inhibitors; Brd4-bound enhancers; glioblastoma; sex differences; sex-specific transcriptional programs
Document Type: Article
Publication Stage: Final
Astrocytes close a motor circuit critical period
(2021) Nature, 592(7854), pp. 414–420
Ackerman, S.D., Perez-Catalan, N.A., Freeman, M.R., Doe, C.Q.
Critical periods—brief intervals during which neural circuits can be modified by activity—are necessary for proper neural circuit assembly. Extended critical periods are associated with neurodevelopmental disorders; however, the mechanisms that ensure timely critical period closure remain poorly understood1,2. Here we define a critical period in a developing Drosophila motor circuit and identify astrocytes as essential for proper critical period termination. During the critical period, changes in activity regulate dendrite length, complexity and connectivity of motor neurons. Astrocytes invaded the neuropil just before critical period closure3, and astrocyte ablation prolonged the critical period. Finally, we used a genetic screen to identify astrocyte–motor neuron signalling pathways that close the critical period, including Neuroligin–Neurexin signalling. Reduced signalling destabilized dendritic microtubules, increased dendrite dynamicity and impaired locomotor behaviour, underscoring the importance of critical period closure. Previous work defined astroglia as regulators of plasticity at individual synapses4; we show here that astrocytes also regulate motor circuit critical period closure to ensure proper locomotor behaviour.