Total Length of Genes = 50 Million Base Pairs

Human Genome

Full Length = 3 Billion Base Pairs

The flow of genetic information from DNA to mRNA to proteins

The identical genetic information is stored in DNA of all cells in our bodies. This requires precise regulation of gene activity so that only the correct set of genes is active in each specific cell type

Interphase

Cell cycle dynamics

Metaphase

Chromosome Territories

Symmetric case

Interphase

Proliferation

Proliferation

Quiescence: Differentiation or Proliferation

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Reprogramming

Symmetric

Symmetric

Asymmetric

Type of Result

Classification

A beautifully controlled process. The quiescent state subsequently leads to proliferation, differentiation, or senescence. improve efficiency of reprogramming by engineering symmetric cell division to a new cell type (red arrows).

Cell cycle

Proliferation

Quiescence

Differentiation

COMPONENTS

Cell cycle

Proliferation

Quiescence

Differentiation

A minimal network (switch) for the proliferation (MYOD1 strongly suppressed by CDK2), quiescence (CDK2 strongly suppressed by P21), or differentiation (P21 strongly activated by MYOD1) decision in myo-genesis.

MINIMAL SYSTEM

My writings: https://docs.google.com/document/d/1wrSJd9PT4KGLqxUXwL_cYoTW69J-2AV9/edit?usp=sharing&ouid=106090800738583027019&rtpof=true&sd=true

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Two Papers:

1. Halevy, Orna, et al. "Correlation of terminal cell cycle arrest of skeletal muscle with induction of p21 by MyoD." Science 267.5200 (1995): 1018-1021. (See Figure 5)
2. Spencer, Sabrina L., et al. "The proliferation-quiescence decision is controlled by a bifurcation in CDK2 activity at mitotic exit." Cell 155.2 (2013): 369-383.

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Cell cycle

The proliferation-quiescence decision is controlled by a bifurcation in CDK2 activity at mitotic exit.pdf

Genome Can Be Decomposed Into Two Parts

Data Background

Genome: Consists of “gene” and intergenic (“non-gene”) parts

Chromosome conformation capture (Hi-C)

RNASeq

“Non-gene” part

Time

Expression

Chromatin accessibility

Transcriptional activity

Chromosome “painting” to capture architecture

Chromosome conformation capture (Hi-C) data showing genome-wide chromatin contacts

Imaging

Biochemically

Sequence

Time

4DN

1D

High-dimensional Dynamical Data

Single cell

Single cell or Population

Basic Features of Genome Organization

From Tom Misteli at National Cancer Institute

Dynamical Data

Dynamical System

Time

Time

. . .

Structure

Function

Dynamical System!

Hi-C: Genome-wide chromosome conformation capture

1MB = 3000 X 3000, 50 BP = 62M X 62M

Hi-C: Graph = Matrix

Pore-C: Hypergraphs

Our Challenge: Convert genome architecture

into data and mathematics

Cell Cycle Dynamics: Single Cell Gene Expression During G1

Blue: Single Cells, Red: Mean Expression

Live Cell Imaging

Cells only

+MYOD1

- PRRX1

Normal Development

Differentiation

Embryonic Stem cell (ES cell)

Tissue Specific Stem cell (TSSC)

All cell types in the human body (estimated to be about 300)

Unidirectional process : Embryo into an adult human

Egg

Sperm

The human body is a finite and dynamical system

• All cells of the body have the same set of genes
• Humans: 37.2 trillion cells
• Adult human typically has around 10,000 hematopoietic stem cells in their bone marrow
• Retinal Pigmented Epithelium of the eye: 50000
• Adult cells of one kind can be converted, either through embryonic cells or directly to cells of unrelated kind
• Therefore, replacement of some types of aged or non-functional cells is possible

This is accomplished via autologous cell reprogramming

Cellular Reprogramming

Induced Pluripotent Stem Cell = Embryonic Stem Cell

Transcription Factors

• Transcription factors (TF) are proteins that bind to DNA
• TFs are often used to mediate reprogramming
• MYOD1 for fibroblast to muscle
• OCT4, SOX2, KLF4, and MYC for fibroblast to iPSC
• TFs bind in specific sequences in promoter and enhancer regions to control gene expression

Controlling Information

modified mRNA

RNA interference

Number of Genes in the Human Genome = 20000

Number of Transcription Factors = 1800

Number of Master Regulators (subset of Transcription Factors) = 800

For simplicity, let us consider three genes in the human genome, G1, G2, and G3. G1 mRNA is T1, and the protein product of G1 is P1. G2 produces mRNA T2 and protein P2, and likewise for G3, T3, and P3. P1 localizes to the nucleus and regulates transcription of G1 and G2. P2 also localizes to the nucleus, but only regulates transcription of G3. Thus, we defined G1 and G2 are transcription factors, whereas G3 is not. G1 is special in that it is a master regulator transcription factor, which can be defined as a self-regulating transcription factor. Figure 1 illustrates this hierarchy. If all genes are classified using this hierarchy, one can construct a universal gene network that is cell type invariant. We call this network the hardwired genome.  

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Hardwired Genome (HWG)

Master Regulator

Transcription Factors

p₁

t₁

p₂

t₂

p₃

t₃

g₁

g₂

g₃

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Hardwired Genome

The Hardwired Genome is a representation of all possible protein-protein interactions in the human genome, created jointly by iReprogram, Inc and University of Michigan. It is built on the Genome Reference Consortium Human Build 38 patch release 13 (GRCh38.p13)

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Elements of the Hardwired Genome

Multi-way Interactions in the Human Genome

My Ultimate Goal: My Cells, My Cure!

PROBLEM

SOLUTION

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Autologous cell reprogramming

Bone-marrow Transplant is the Treatment for the Treatment