Explore the intricacies of large-scale nuclear architecture in this comprehensive lecture by Gautam Menon from Ashoka University/IMSc, India. Delve into the fascinating world of biophysics, computational biology, and infectious diseases as the speaker addresses the challenge of bringing rigorous physical modeling to biological systems. Learn about the complex organization of chromosomes within the nucleus, including chromosome territories and the differences between euchromatin and heterochromatin. Discover how energy-consuming processes and mechanical forces influence chromatin behavior, and examine experimental data alongside theoretical predictions. Investigate the distribution of chromosomes based on size and gene density, and explore the concept of nuclear phase separation. Gain insights into cutting-edge research on nucleolus formation and the differential localization of active and inactive X chromosomes. This in-depth presentation offers a valuable perspective on the intersection of physics and biology in understanding nuclear architecture.
Understanding Large-Scale Nuclear Architecture by Gautam Menon
International Centre for Theoretical Sciences via YouTube
Overview
Syllabus
Gautama Menon Ashoka University/IMSc, India 04:30 pm, 18 JANUARY 2021
Biophysics Computational Biology Infectious diseases
Can one bring to biological modelling the rigor of models in physics?
Can one bring to biological modelling the rigor and precision of models in physics?
What would we call progress in the quantitative model understanding of specific systems in biology?
All of us work with mental models
Leave out detail, capture essential features as the ultimate goal .... but what details?
The question I've been interested in
Metazoans
A single cell
What makes a simple polymer different from DNA in the nucleus of a living cell?
Term "chromatin" coined in 1882 by Walther Flemming to
Talk about chromatin when we discuss the
"During the 1970s and 1980s, most researchers seemed content with the assumption that
What we know now
Chromosomes are not mixed at random but are found in well-defined territories
How do we know this? Chromosome painting
Tightly packed DNA, gene-poor
What makes a simple polymer different from DNA in the nucleus of a living cell?
The biophysical context
What does it mean to say something is not in thermal equilibrium? Currents flow through
Drive a system out of equilibrium by adding energy on a
ATP hydrolysis
1. Chromosomes are territorial
Quantifying non-random arrangements?
Challenge Predict these
"Stylised facts"
SR = 4TR2 PIR
Hypothesis
Chromatin in living cells has many energy consuming
More active regions: Chromatin should see larger mechanical forces
Different gene densities in
More active: Larger fluctuations.
Simplest model
Simulate individual chromosomes within a nucleus
Gene-poor, less active chromatin heterochromatin
Experimental data
Theoretical Predictions
Chromosome Territories: Rabl 1885, Boveri 1908, Stack 1977
Simulations starting from many different initial conditions.
Centre of Mass Distribution
Also agree with our broad understanding from lots of different measurements, which is encouraging
Simplest model surprisingly
GM12878
SOM R
Euchromatin & Heterochromatin
DNA density distribution: 12/20
Configurations: Chromosomes 18 and 19 2 homologs each
Are chromosomes distributed by their gene density or by their size?
Chromosome size
Chromosome gene density
GM12878 Insitu
GM12878 TCC
The fractional volume occupied by each chromosome, as a function of its length
Inactive X chromosome located more peripherally than the active X
Xa/Xi differential localizations
A first-principles model
Nucleolus formation Nuclear phase separation
Collaborators
Thank you
Taught by
International Centre for Theoretical Sciences
