The hardwiring of development organization and function of genomic regulatory systems
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The Hardwiring of development: organization and function of genomic regulatory systems. Maria I. Arnone and Eric H. Davidson. Outline:. Introduction Properties of CIS-Regulatory Systems Gene Regulatory Networks Conclusion and Summary. Introduction.

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The Hardwiring of development: organization and function of genomic regulatory systems

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The Hardwiring of development: organization and function of genomic regulatory systems

Maria I. Arnone and Eric H. Davidson


Outline:

  • Introduction

  • Properties of CIS-Regulatory Systems

  • Gene Regulatory Networks

  • Conclusion and Summary


Introduction

  • Regulatory program is hardwired into genomic DNA sequence

  • CIS-regulatory target sites are recognized sequences-specifically by T.F

  • Control Rate, activation, repression, time and morphological space

  • Reveals internal working and interconnections i.e., structure of gene regulatory network


  • CIS-regulatory systems are complex

  • Objective is to understand the flow of regulatory information from the genome to understand development

  • Inputs and outputs studied…., but…

  • To find out how genomic regulatory systems really work, examination of the CIS sequence themselves is necessary


Properties of CIS-Regulatory Systems

  • Regulatory modules: Separate CIS elements, multiple T.F target sites

  • Can transmit output to BTA

  • Communication achieved by T.F anchored or proteins that bind T.F

  • Long distance achieved by DNA looping

  • Works with promoters i.e. platform on which BTA assembles

  • Novel expression constructs can be created


Intramodular Complexity

  • Complexity is number of diverse interactions, i.e., T.F bound per module

  • Most cases complexity is underestimated

  • Avg. # of interactions is 6.2

  • Factors are of diverse chemical nature, no modules serviced by only homeodomain proteins or Zn finger proteins.


Significance of DNA-protein interactions detected in vitro

  • Does binding imply significance?

  • Three reasons

    • Equilibrium constants

    • When affinity is low, cooperative interactions stabilize it

    • Length of sequence protected by bound T.F specify these sites uniquely

      Various experiments done to show that sequence preference of T.F for its target site is at least 5-10*103

      Interference produces distinct phenotype

      Therefore target site code in CIS region is meaningful at this specificity.


Positive and Negative functions of factors binding within cis-regulatory modules

  • Modular elements target of T.F with diverse functions

  • Focus on activation and repression

  • Maternal factors in embryo

  • Mutation in repressor modules => ectopic expression

  • Mutation in activator target sites => lower level of normal expression

  • Activators and repressors act in conjunction to regulate genes


Programming communication within complex cis-regulatory systems

  • Many CIS regulatory elements interact at both near and far distances, ex: by forming loops

  • Dwell time for the complexes is 15-80mins

  • Proximal CIS-regulatory modules process outputs of distally located modules

  • Interactions increase diversity of control functions of CIS system

  • Looping occurs due to affinity of proteins

  • Intermodular communication is therefore hardwired


Cis-regulatory organization as an index of developmental role

  • Goal is to use cis-regulatory target sites to predict role in regulation and position in network.

  • Modules that interpret embryonic spatial specification bind activators and repressors

  • Ones that use only positive regulators likely to act downstream

  • T.F confined to spatial domains and serve as activators in downstream genes in particular regions

  • CIS regulators of these genes may operate by activation as well as repression


Gene Regulatory Networks

  • Linkage between different cis-regulatory systems together with genes that they govern

  • Batteries of genes that encode cell-type-specific differentiation proteins

  • Linkage between genes that encode T.F and differentiation proteins


Gene batteries

  • Sets of genes expressed in different stages of development

  • Genes that are coordinately expressed because their cis-regulatory sequences share homologous sites for TF

  • But, TF for which genes of a battery share sites are not cell-type specific

  • Order and spacing of target sites not alike in any two genes of same cell type

  • Reflects lack of functions constraint i.e. spacing and order

  • Battery relations can only be elucidated by direct analysis

  • Analysis of batteries will help to go from protein of known function to interior of gene regulatory network


General Considerations

  • Peripheral and internal network elements:

    • Linkage to CIS only upstream or both upstream and downstream i.e. TF

      Network and Casual relationships:

    • Refer to figure

      Multilevel connections:

    • Downstream connections from internal genes to peripheral genes

    • Autoregulatory connections

    • Therefore network cannot be considered hierarchical


View from the genome and View from the nucleus

  • Figures show view from genome

  • View from nucleus describes developmental state

  • CIS region may be fully loaded, partially loaded or empty depending on state of cell

  • Per-genome networks have no temporal dependence

  • Per-nuclear networks depend on time


Complexity of developmental gene regulation

  • # of linkages upstream from a cis-regulatory system

  • Integration of spatial information to regulate TF during growth and cellular expansion

  • Complex network linkages even in early developmental stages

  • Initially transcribed peripheral genes from maternal effect may have shallow regulatory network and therefore may be within reach for regulatory analysis


Conclusion

  • Importance of cis-regulatory analysis

  • Path to understand the organization of the genomic program for development.

  • Analyzing networks will lead to solving developmental and evolutionary questions

  • Primary genomic sequence data will be most important


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