Christoph Cremer and Thomas Cremer 40 years of joint ... - TLB

Christoph Cremer and Thomas Cremer
40 years of joint research to explore the functional nuclear
architecture
Thomas Cremer
From experimental proof of chromosome territories to the chromosome
territory - interchromatin compartment (CT-IC) model
Biocenter, Department Biology II, Anthropology and Human Genetics,
Ludwig Maximilians University (LMU) Munch, D-82152 Martinsried, Germany e-mail:
Thomas. Cremer@lrz. uni-muenchen. de
The hypothesis of chromosome territories (CTs) was first proposed by Carl Rabl
(1885) and Theodor Boveri (1909), but later abandoned. In 1969, at this time one
of us (C. Cremer) was still a physics student, while the other (T. Cremer) studied
human medicine, we proposed a construction plan for a laser-uv-microbeam (257
nm) and pointed out the possibility to study higher order chromatin organization with
such a device:
"Does a non-random arrangement of chromosomes exist in the interphase
nucleus, which may possibly change during different functional states? For
example, might genes, which belong functionally together be located in close
neighborhood, even when they are located on different chromosomes? In such a
case, a method, which allows the generation of isolated damage of small nuclear
areas, may lead to the establishment of statistically significant linkage groups." (C. &
T. Cremer, 1969: Translation of the German original.)
This proposal formed the basis of a project funded since 1971 by the German
Research Foundation (DFG), which led to experimental evidence in favor of the
Rabl/Boveri hypothesis.
During the 1980ies several groups obtained direct evidence for chromosome
territories. Since then we have developed methods for quantitative studies of CT
organization and arrangements in the cell nucleus. The results of these studies led to
the CT-IC model of nuclear architecture.
The interchromatin-compartment (IC) forms an interconnected 3D system of ICchannels
(width 400 nm). It starts/ends with small
channels at the nuclear pores and expands both between CTs and throughout the
interior of CTs. Splicing speckles and nuclear bodies are located within the IC and
recent evidence suggests that the IC also serves as a preferred route for the
transport of RNPs.
CTs are built up from a network of interconnected ~1 Mb chromatin domains
(~1Mb CDs), i.e. domains with a DNA-content in the order of 1 Mb. Clusters of
~1Mb CDs can form still larger CDs. Replicating ~1Mb CDs can be visualized during
S-phase as replication foci, but they persist as basic units of higher order
Christoph & Thomas Cremer, 40 years of joint research 1

chromatin organization at any stage of interphase.
To which extent ~1Mb CDs persist as indivdidual entitities during the transformation
of CTs into mitotic chromosomes and into nuclei of the next cell generation remains
to be established. The structure of ~1Mb CDs has not yet been resolved, but we
argue that each ~1Mb CD is built up from a series of ~100 kb chromatin domains
(~100 kb CDs), i.e. more or less compacted chromatin loop domains with a DNA
content in the order of 100 kb.
Direct contacts between neighboring ~1Mb CDs provide ample opportunities for
interactions in cis (within a given CT) or trans (between neighboring CTs),
including the formation of intra- and interchromosomal rearrangements.
The perichromatin region (PR) represents an about 100 nm thick layer of
decondensed chromatin, located at the periphery of CDs. It constitutes the nuclear
compartment for transcription, splicing, DNA-replication and possibly also DNArepair
and separates the highly compact, transcriptionally silent interior of CDs
from the IC.
Accordingly the 3D organization of a CT can be compared with a sponge built up
from a 3D network of chromatin domains permeated by the IC. It should be noted
that constrained Brownian movements of CDs in the nucleus of living cells result in
continuous changes of the width of IC channels providing dynamic opportunities
for normal or pathological interactions.
The interior of IC lacunas is free of chromatin and harbors nuclear bodies and
splicing speckles. This structural organization allows direct functional interactions
between the IC and the PR, such as the delivery of splicing components from splicing
speckles to sites of co-transcriptional splicing.
For Reviews see:
Cremer C, Cremer T (1971) 4Π Punkthologramme: Physikalische Grundlagen und mögliche
Anwendungen. Enclosure to Patent application DE 2116521 „Verfahren zur Darstellung bzw.
Modifikation von Objekt-Details, deren Abmessungen außerhalb der sichtbaren Wellenlängen
liegen" (Procedure for the imaging and modification of object details with dimensions beyond the
visible wavelengths). Filed April 5, 1971; publication date October 12, 1972.Deutsches Patentamt,
Berlin.
Cremer T, Cremer C (2001) Chromosome Territories Nuclear Architecture and Gene
Regulation in Mammalian Cells. Nature Reviews Genetics 2: 292-301.
Cremer T, Cremer C (2006) Rise, fall and resurrection of chromosome territories: a historical
perspective. Part I. The rise of chromosome territories. Eur J Histochem 50: 161-176.
Cremer, T, Cremer C (2006) Rise, fall and resurrection of chromosome territories: a historical
perspective. Part II. Fall and resurrection of chromosome territories during the 1950s to 1980s. Part
III. Chromosome territories and the functional nuclear architecture: experiments and models from the
1990s to the present. Eur J Histochem 50: 223-272.
Markaki Y, Gunkel M, Schermelleh L, Beichmanis S, Neumann J, Heidemann M, Leonhardt H,
Eick D,Cremer C, Cremer T (2010) Functional nuclear organization of transcription and DNA
replication: a topographical marriage between chromatin domains and the interchromatin
compartment. Cold Spring Harb. Sym. Quant. Biol. 75: 475-492.
Christoph & Thomas Cremer, 40 years of joint research 2