Rao, K. S. | Search bioRxiv

bioRxiv2019

A TBX5 dosage-sensitive gene regulatory network for human congenital heart disease

Haploinsufficiency of transcriptional regulators causes human congenital heart disease (CHD). However, underlying CHD gene regulatory network (GRN) imbalances are unknown. Here, we define transcriptional consequences of reduced dosage of the CHD-linked transcription factor, TBX5, in individual cells during cardiomyocyte differentiation from human induced pluripotent stem cells (iPSCs). We discovered highly sensitive dysregulation of TBX5-dependent pathways-- including lineage decisions and genes associated with cardiomyocyte function and CHD genetics--in discrete subpopulations of cardiomyocytes. GRN analysis identified vulnerable nodes enriched for CHD genes, indicating that cardiac network stability is sensitive to TBX5 dosage. A GRN-predicted genetic interaction between Tbx5 and Mef2c was validated in mouse, manifesting as ventricular septation defects. These results demonstrate exquisite sensitivity to TBX5 dosage by diverse transcriptional responses in heterogeneous subsets of iPSC-derived cardiomyocytes. This predicts candidate GRNs for human CHDs, with implications for quantitative transcriptional regulation in disease.

developmental biology↗

bioRxiv2019

Persons post-stroke restore step length symmetry by walking asymmetrically

BackgroundRestoration of step length symmetry is a common rehabilitation goal after stroke. Persons post-stroke often retain the capacity to walk with symmetric step lengths (\"symmetric steps\"); however, the resulting walking pattern remains effortful. Two key questions with direct implications for rehabilitation have emerged: 1) how do persons post-stroke generate symmetric steps, and 2) why do symmetric steps remain so effortful?\n\nObjectiveTo understand how persons post-stroke generate symmetric steps and how the resulting gait pattern relates to the metabolic cost of transport.\n\nMethodsTen persons post-stroke walked on an instrumented treadmill under two conditions: preferred walking and symmetric stepping (using visual feedback). We recorded kinematic, kinetic, and metabolic data during both conditions.\n\nResultsPersons post-stroke restored step length symmetry using energetically expensive, asymmetric patterns. Impaired paretic propulsion and abnormal vertical movement of the center of mass were evident during both preferred walking and symmetric stepping. These deficits contributed to diminished positive work performed by the paretic limb on the center of mass in both conditions. Decreased positive paretic work correlated with increased metabolic cost of transport, decreased self-selected walking speed, and increased asymmetry in limb kinematics.\n\nConclusionsIt is important to consider the mechanics used to restore symmetric steps when designing interventions to improve walking after stroke. Facilitating symmetric steps via increased paretic propulsion or enabling paretic limb advancement without excessive vertical movement may enable persons post-stroke to walk with a less effortful, more symmetric gait pattern.

neuroscience↗